Exomiser

https://exomiser.readthedocs.io/en/stable/
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Exomiser is a Java program for finding potential disease-causing variants in whole-exome or...
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### Install via Homebrew

Source: https://exomiser.readthedocs.io/en/stable/_sources/installation.rst.txt

Commands to install Exomiser using Homebrew and verify the generated directory structure.

```bash
brew install exomiser/tap/exomiser
```

```bash
$ tree ~/.exomiser
/home/user/.exomiser
├── application.properties
└── data
```

--------------------------------

### Example Output File Paths

Source: https://exomiser.readthedocs.io/en/stable/input_files_and_options.html

Shows the default file structure for generated analysis results.

```text
exomiser-cli-15.1.0/results/manuel_exomiser.html
exomiser-cli-15.1.0/results/manuel_exomiser.json
exomiser-cli-15.1.0/results/manuel_exomiser.parquet
```

--------------------------------

### Exomiser Output File List

Source: https://exomiser.readthedocs.io/en/stable/_sources/input_files_and_options.rst.txt

Example of the files generated in the results directory after an analysis.

```text
exomiser-cli-|version|/results/manuel_exomiser.html
exomiser-cli-|version|/results/manuel_exomiser.json
exomiser-cli-|version|/results/manuel_exomiser.parquet
```

--------------------------------

### Java Version Output Example

Source: https://exomiser.readthedocs.io/en/stable/installation.html

Expected output format when running the Java version check command.

```text
openjdk 21.0.6 2025-01-21
OpenJDK Runtime Environment (build 21.0.6+7-Ubuntu-124.04.1)
OpenJDK 64-Bit Server VM (build 21.0.6+7-Ubuntu-124.04.1, mixed mode, sharing)

```

--------------------------------

### Install Exomiser on Linux/macOS

Source: https://exomiser.readthedocs.io/en/stable/installation.html

Commands to download, extract, and prepare the Exomiser application and data files on Unix-based systems.

```bash
# Download the Exomiser program (small, fast)
wget https://github.com/exomiser/Exomiser/releases/download/exomiser-cli-15.1.0-distribution.zip

# Download the data files (large — allow several hours)
# If you only need one genome assembly, download only the relevant file.
wget https://g-879a9f.f5dc97.75bc.dn.glob.us/data/2512_phenotype.zip
wget https://g-879a9f.f5dc97.75bc.dn.glob.us/data/2512_hg38.zip
wget https://g-879a9f.f5dc97.75bc.dn.glob.us/data/2512_hg19.zip

# Extract the program
unzip exomiser-cli-15.1.0-distribution.zip

# Extract the data files into the data subdirectory
unzip 2512_*.zip -d exomiser-cli-15.1.0/data

# Navigate into the Exomiser folder
cd exomiser-cli-15.1.0
```

--------------------------------

### Run Test Analysis on Windows

Source: https://exomiser.readthedocs.io/en/stable/_sources/installation.rst.txt

Navigate to the installation directory and execute the test analysis using the command prompt.

```bash
cd exomiser-cli-|version|
java -jar exomiser-cli-|version|.jar analyse --analysis examples/test-analysis-exome.yml
```

--------------------------------

### Exomiser Batch Command File

Source: https://exomiser.readthedocs.io/en/stable/_sources/input_files_and_options.rst.txt

Example content for a batch file containing multiple analysis commands.

```text
#This is an example analysis batch file to be run using the --analysis-batch command
#
#Each line should specify the path of a single analysis file, either relative to the directory the exomiser
#is being run from or the full system path. It will run any combination of exomiser commands listed using -h or --help.
#
# Original format exomiser analysis containing all the sample and analysis information
--analysis test-analysis-exome.yml
# New preset exome analysis using a v1 phenopacket to submit the phenotype information and adding/overriding the VCF input
--preset exome --sample pfeiffer-phenopacket.yml --vcf Pfeiffer.vcf.gz
# Using the default analysis (exome) with a v1 phenopacket containing the phenotype information and adding/overriding the VCF input
--sample pfeiffer-phenopacket.yml --vcf Pfeiffer.vcf.gz
# Using a user-defined analysis with a v1 phenopacket containing the phenotype information and adding/overriding the VCF input
--analysis preset-exome-analysis.yml --sample pfeiffer-phenopacket.yml --vcf Pfeiffer.vcf.gz
# Using a user-defined analysis with a v1 phenopacket containing the phenotype information and adding/overriding the VCF input
--analysis preset-exome-analysis.yml --sample pfeiffer-phenopacket.yml --vcf Pfeiffer.vcf.gz --output output-options.yml
```

--------------------------------

### Run Test Analysis

Source: https://exomiser.readthedocs.io/en/stable/installation.html

Command to execute a test analysis to verify the installation is functioning correctly.

```bash
cd exomiser-cli-15.1.0
java -jar exomiser-cli-15.1.0.jar analyse --analysis examples/test-analysis-exome.yml
```

--------------------------------

### Run from Alternate Directory

Source: https://exomiser.readthedocs.io/en/stable/_sources/running.rst.txt

Executes Exomiser when the working directory differs from the installation directory, requiring an explicit path to application.properties.

```bash
 java -Dspring.config.location=/full/path/to/your/exomiser-cli/directory/application.properties \
 -jar /full/path/to/your/exomiser-cli/directory/exomiser-cli-|version|.jar analyse \
 --sample /full/path/to/your/exomiser-cli/directory/examples/pfeiffer-phenopacket.yml \
 --vcf /full/path/to/your/exomiser-cli/directory/examples/Pfeiffer.vcf.gz --assembly hg19 \
 --output-directory full/path/to/your/results/directory
```

--------------------------------

### Exomiser Parquet Result Preview

Source: https://exomiser.readthedocs.io/en/stable/_sources/result_interpretation.rst.txt

Example of the Parquet output format, which can be inspected using tools like DuckDB.

```text
     rank      variant                    geneSymbol       hgncId         ensemblGeneId      ncbiGeneId  moi       pValue    geneCombinedScore  genePhenotypeScore  geneVariantScore  variantScore  isContributingVariant  isWhiteListVariant  faile
   ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
     1         "10-123256215-T-G_AD"      "FGFR2"          "HGNC:3689"    "ENSG00000066468"  "2263"      "AD"      0.000002  0.97066            0.87752             1.0               1.0           true                   true                []
     2         "6-132203615-G-A_AD"       "ENPP1"          "HGNC:3356"    "ENSG00000197594"  "5167"      "AD"      0.000162  0.711517           0.62356             1.0               1.0           true                   true                []
     3         "7-76069617-TG-T_AD"       "ZP3"            "HGNC:13189"   "ENSG00000188372"  "7784"      "AD"      0.001186  0.400489           0.502852            0.995171          0.995171      true                   false               []
     4         "13-110855918-C-G_AD"      "COL4A1"         "HGNC:2202"    "ENSG00000187498"  "1282"      "AD"      0.049614  0.026842           0.506021            0.985988          0.985988      true                   false               []
```

--------------------------------

### Configure Pathogenicity Sources

Source: https://exomiser.readthedocs.io/en/stable/_sources/advanced_analysis.rst.txt

Example configuration for specifying pathogenicity sources in YAML format.

```yaml
pathogenicitySources: [REVEL, MVP, REMM]
```

--------------------------------

### Parquet Data Preview

Source: https://exomiser.readthedocs.io/en/stable/result_interpretation.html

Example of the tabular data structure found within the Parquet output.

```text
  rank      variant                    geneSymbol       hgncId         ensemblGeneId      ncbiGeneId  moi       pValue    geneCombinedScore  genePhenotypeScore  geneVariantScore  variantScore  isContributingVariant  isWhiteListVariant  faile
─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
  1         "10-123256215-T-G_AD"      "FGFR2"          "HGNC:3689"    "ENSG00000066468"  "2263"      "AD"      0.000002  0.97066            0.87752             1.0               1.0           true                   true                []
  2         "6-132203615-G-A_AD"       "ENPP1"          "HGNC:3356"    "ENSG00000197594"  "5167"      "AD"      0.000162  0.711517           0.62356             1.0               1.0           true                   true                []
  3         "7-76069617-TG-T_AD"       "ZP3"            "HGNC:13189"   "ENSG00000188372"  "7784"      "AD"      0.001186  0.400489           0.502852            0.995171          0.995171      true                   false               []
  4         "13-110855918-C-G_AD"      "COL4A1"         "HGNC:2202"    "ENSG00000187498"  "1282"      "AD"      0.049614  0.026842           0.506021            0.985988          0.985988      true                   false               []
```

--------------------------------

### Check Java Version

Source: https://exomiser.readthedocs.io/en/stable/_sources/installation.rst.txt

Verify the installed Java version to ensure it meets the minimum requirement of version 21.

```bash
java -version
```

--------------------------------

### Configure Exomiser via JAVA_TOOL_OPTIONS

Source: https://exomiser.readthedocs.io/en/stable/_sources/installation.rst.txt

Use the JAVA_TOOL_OPTIONS environment variable to set data paths and versions when using Homebrew installations.

```bash
export JAVA_TOOL_OPTIONS="-Dexomiser.data-directory=/full/path/to/exomiser-data -Dexomiser.hg38.data-version=2512"
```

--------------------------------

### Check Java Version

Source: https://exomiser.readthedocs.io/en/stable/_sources/installation.rst.txt

Verify the installed Java version to ensure it meets the requirement of Java 21 or higher.

```console
$ java -version
```

```console
openjdk 21.0.6 2025-01-21
OpenJDK Runtime Environment (build 21.0.6+7-Ubuntu-124.04.1)
OpenJDK 64-Bit Server VM (build 21.0.6+7-Ubuntu-124.04.1, mixed mode, sharing)
```

--------------------------------

### Full Exomiser Analysis Job Configuration

Source: https://exomiser.readthedocs.io/en/stable/advanced_analysis.html

A comprehensive example of an Exomiser analysis job file defining modes, frequency sources, pathogenicity sources, and processing steps.

```yaml
---
analysisMode: PASS_ONLY
inheritanceModes: {
  AUTOSOMAL_DOMINANT: 0.1,
  AUTOSOMAL_RECESSIVE_HOM_ALT: 0.1,
  AUTOSOMAL_RECESSIVE_COMP_HET: 2.0,
  X_DOMINANT: 0.1,
  X_RECESSIVE_HOM_ALT: 0.1,
  X_RECESSIVE_COMP_HET: 2.0,
  MITOCHONDRIAL: 0.2
}
frequencySources: [
    THOUSAND_GENOMES,
    TOPMED,
    UK10K,

    ESP_AA, ESP_EA, ESP_ALL,

    GNOMAD_E_AFR,
    GNOMAD_E_AMR,
  #        GNOMAD_E_ASJ,
    GNOMAD_E_EAS,
    GNOMAD_E_FIN,
    GNOMAD_E_NFE,
    GNOMAD_E_OTH,
    GNOMAD_E_SAS,

    GNOMAD_G_AFR,
    GNOMAD_G_AMR,
  #        GNOMAD_G_ASJ,
    GNOMAD_G_EAS,
    GNOMAD_G_FIN,
    GNOMAD_G_NFE,
    GNOMAD_G_OTH,
    GNOMAD_G_SAS
]
# Possible pathogenicitySources: (POLYPHEN, MUTATION_TASTER, SIFT), (REVEL, MVP, ALPHA_MISSENSE), CADD, REMM
# REMM is trained on non-coding regulatory regions
# *WARNING* if you enable CADD or REMM ensure that you have downloaded and installed the CADD/REMM tabix files
# and updated their location in the application.properties. Exomiser will not run without this.
pathogenicitySources: [ REVEL, MVP, ALPHA_MISSENSE ]
#this is the standard exomiser order.
steps: [
    failedVariantFilter: { },
    variantEffectFilter: {
      remove: [
          FIVE_PRIME_UTR_EXON_VARIANT,
          FIVE_PRIME_UTR_INTRON_VARIANT,
          THREE_PRIME_UTR_EXON_VARIANT,
          THREE_PRIME_UTR_INTRON_VARIANT,
          NON_CODING_TRANSCRIPT_EXON_VARIANT,
          NON_CODING_TRANSCRIPT_INTRON_VARIANT,
          CODING_TRANSCRIPT_INTRON_VARIANT,
          UPSTREAM_GENE_VARIANT,
          DOWNSTREAM_GENE_VARIANT,
          INTERGENIC_VARIANT,
          REGULATORY_REGION_VARIANT
      ]
    },
    frequencyFilter: { maxFrequency: 2.0 },
    pathogenicityFilter: { keepNonPathogenic: true },
    inheritanceFilter: { },
    omimPrioritiser: { },
    hiPhivePrioritiser: { }
]
```

--------------------------------

### Unsupported Java Version Error

Source: https://exomiser.readthedocs.io/en/stable/installation.html

Error messages indicating that the installed Java runtime is incompatible with the compiled Exomiser classes.

```text
Exception in thread "main" java.lang.UnsupportedClassVersionError:
org/monarchinitiative/exomiser/cli/Main : Unsupported major.minor version

```

```text
Error: A JNI error has occurred, please check your installation and try again
Exception in thread "main" java.lang.UnsupportedClassVersionError: org/monarchinitiative/exomiser/cli/Main has been
compiled by a more recent version of the Java Runtime (class file version 55.0), this version of the Java Runtime
only recognizes class file versions up to 52.0

```

--------------------------------

### Display Exomiser Help

Source: https://exomiser.readthedocs.io/en/stable/_sources/running.rst.txt

Use this command to view available CLI options and help documentation.

```bash
java -jar exomiser-cli-|version|.jar --help
```

--------------------------------

### Exomiser VCF INFO Field Definition and Example Data

Source: https://exomiser.readthedocs.io/en/stable/result_interpretation.html

The INFO field contains pipe-separated values for compatible modes of inheritance. This example shows the header definition and sample variant records.

```text
##INFO=<ID=Exomiser,Number=.,Type=String,Description="A pipe-separated set of values for the proband allele(s) from the record with one per compatible MOI following the format: {RANK|ID|GENE_SYMBOL|ENTREZ_GENE_ID|MOI|P-VALUE|EXOMISER_GENE_COMBINED_SCORE|EXOMISER_GENE_PHENO_SCORE|EXOMISER_GENE_VARIANT_SCORE|EXOMISER_VARIANT_SCORE|CONTRIBUTING_VARIANT|WHITELIST_VARIANT|FUNCTIONAL_CLASS|HGVS|EXOMISER_ACMG_CLASSIFICATION|EXOMISER_ACMG_EVIDENCE|EXOMISER_ACMG_DISEASE_ID|EXOMISER_ACMG_DISEASE_NAME}">
#CHROM      POS     ID      REF     ALT     QUAL    FILTER  INFO    sample
10  123256215       .       T       G       100     PASS    Exomiser={1|10-123256215-T-G_AD|FGFR2|2263|AD|0.0000|0.9981|1.0000|1.0000|1.0000|1|1|missense_variant|FGFR2:ENST00000346997.2:c.1688A>C:p.(Glu563Ala)|LIKELY_PATHOGENIC|PM2&PP3_Strong&PP4&PP5|OMIM:123150|"Jackson-Weiss syndrome"};GENE=FGFR2;INHERITANCE=AD;MIM=101600       GT:DS:PL        1|0:2.000:50,11,0
11  1018088 .       TG      T       441.81  PASS    AC=1;AF=0.50;AN=2;BaseQRankSum=7.677;DP=162;DS;Exomiser={7|11-1018088-TG-T_AD|MUC6|4588|AD|0.0096|0.7532|0.5030|0.9990|0.9990|1|0|frameshift_variant|MUC6:ENST00000421673.2:c.4712del:p.(Pro1571Hisfs*21)|UNCERTAIN_SIGNIFICANCE|||""},{8|11-1018088-TG-T_AR|MUC6|4588|AR|0.0096|0.7531|0.5030|0.9990|0.9990|1|0|frameshift_variant|MUC6:ENST00000421673.2:c.4712del:p.(Pro1571Hisfs*21)|UNCERTAIN_SIGNIFICANCE|||""};FS=25.935;HRun=3;HaplotypeScore=1327.2952;MQ=43.58;MQ0=6;MQRankSum=-5.112;QD=2.31;ReadPosRankSum=2.472;set=variant        GT:AD:DP:GQ:PL  0/1:146,45:162:99:481,0,5488
11  1018093 .       G       GT      592.45  PASS    AC=1;AF=0.50;AN=2;BaseQRankSum=8.019;DP=157;Exomiser={7|11-1018093-G-GT_AD|MUC6|4588|AD|0.0096|0.7532|0.5030|0.9990|0.9989|0|0|frameshift_elongation|MUC6:ENST00000421673.2:c.4707dup:p.(Pro1570Thrfs*136)|NOT_AVAILABLE|||""},{8|11-1018093-G-GT_AR|MUC6|4588|AR|0.0096|0.7531|0.5030|0.9990|0.9989|1|0|frameshift_elongation|MUC6:ENST00000421673.2:c.4707dup:p.(Pro1570Thrfs*136)|UNCERTAIN_SIGNIFICANCE|||""};FS=28.574;HRun=1;HaplotypeScore=1267.6968;MQ=44.06;MQ0=4;MQRankSum=-5.166;QD=3.26;ReadPosRankSum=1.328;set=variant    GT:AD:DP:GQ:PL  0/1:140,42:157:99:631,0,4411
6   132203615       .       G       A       922.98  PASS    AC=1;AF=0.50;AN=2;BaseQRankSum=-0.671;DP=94;Dels=0.00;Exomiser={2|6-132203615-G-A_AD|ENPP1|5167|AD|0.0049|0.8690|0.5773|0.9996|0.9996|1|0|splice_donor_variant|ENPP1:ENST00000360971.2:c.2230+1G>A:p.?|UNCERTAIN_SIGNIFICANCE|PVS1_Strong|OMIM:615522|"Cole disease"};FS=0.805;HRun=0;HaplotypeScore=3.5646;MQ=56.63;MQ0=0;MQRankSum=1.807;QD=9.82;ReadPosRankSum=-0.900;set=variant2   GT:AD:DP:GQ:PL  0/1:53,41:94:99:953,0,1075
```

--------------------------------

### Exomiser TSV Result Format

Source: https://exomiser.readthedocs.io/en/stable/_sources/result_interpretation.rst.txt

Example of the tab-separated values format used for Exomiser results.

```text
#RANK	ID	GENE_SYMBOL	ENTREZ_GENE_ID	MOI	P-VALUE	EXOMISER_GENE_COMBINED_SCORE	EXOMISER_GENE_PHENO_SCORE	EXOMISER_GENE_VARIANT_SCORE	EXOMISER_VARIANT_SCORE	CONTRIBUTING_VARIANT	WHITELIST_VARIANT	VCF_ID	RS_ID	CONTIG	START	END	REF	ALT	CHANGE_LENGTH	QUAL	FILTER	GENOTYPE	FUNCTIONAL_CLASS	HGVS	EXOMISER_ACMG_CLASSIFICATION	EXOMISER_ACMG_EVIDENCE	EXOMISER_ACMG_DISEASE_ID	EXOMISER_ACMG_DISEASE_NAME	CLINVAR_VARIANT_ID	CLINVAR_PRIMARY_INTERPRETATION	CLINVAR_STAR_RATING	GENE_CONSTRAINT_LOEUF	GENE_CONSTRAINT_LOEUF_LOWER	GENE_CONSTRAINT_LOEUF_UPPER	MAX_FREQ_SOURCE	MAX_FREQ	ALL_FREQ	MAX_PATH_SOURCE	MAX_PATH	ALL_PATH
1	10-123256215-T-G_AD	FGFR2	2263	AD	0.0000	0.9981	1.0000	1.0000	1.0000	1	1		rs121918506	10	123256215	123256215	T	G	0	100.0000	PASS	1|0	missense_variant	FGFR2:ENST00000346997.2:c.1688A>C:p.(Glu563Ala)	LIKELY_PATHOGENIC	PM2,PP3_Strong,PP4,PP5	OMIM:123150	Jackson-Weiss syndrome	28333	LIKELY_PATHOGENIC	1	0.13692	0.074	0.27				REVEL	0.965	REVEL=0.965,MVP=0.9517972
2	6-132203615-G-A_AD	ENPP1	5167	AD	0.0049	0.8690	0.5773	0.9996	0.9996	1	0		rs770775549	6	132203615	132203615	G	A	0	922.9800	PASS	0/1	splice_donor_variant	ENPP1:ENST00000360971.2:c.2230+1G>A:p.?	UNCERTAIN_SIGNIFICANCE	PVS1_Strong	OMIM:615522	Cole disease		NOT_PROVIDED	0	0.41042	0.292	0.586	GNOMAD_E_SAS	0.0032486517	TOPMED=7.556E-4,EXAC_NON_FINNISH_EUROPEAN=0.0014985314,GNOMAD_E_NFE=0.0017907989,GNOMAD_E_SAS=0.0032486517
//
7	11-1018088-TG-T_AD	MUC6	4588	AD	0.0096	0.7532	0.5030	0.9990	0.9990	1	0		rs765231061	11	1018088	1018089	TG	T	-1	441.8100	PASS	0/1	frameshift_variant	MUC6:ENST00000421673.2:c.4712del:p.(Pro1571Hisfs*21)	UNCERTAIN_SIGNIFICANCE				NOT_PROVIDED	0	0.79622	0.656	0.971	GNOMAD_G_NFE	0.0070363074	GNOMAD_E_AMR=0.0030803352,GNOMAD_G_NFE=0.0070363074
7	11-1018093-G-GT_AD	MUC6	4588	AD	0.0096	0.7532	0.5030	0.9990	0.9989	0	0		rs376177791	11	1018093	1018093	G	GT	1	592.4500	PASS	0/1	frameshift_elongation	MUC6:ENST00000421673.2:c.4707dup:p.(Pro1570Thrfs*136)	NOT_AVAILABLE				NOT_PROVIDED	0	0.79622	0.656	0.971	GNOMAD_G_NFE	0.007835763	GNOMAD_G_NFE=0.007835763
8	11-1018088-TG-T_AR	MUC6	4588	AR	0.0096	0.7531	0.5030	0.9990	0.9990	1	0		rs765231061	11	1018088	1018089	TG	T	-1	441.8100	PASS	0/1	frameshift_variant	MUC6:ENST00000421673.2:c.4712del:p.(Pro1571Hisfs*21)	UNCERTAIN_SIGNIFICANCE				NOT_PROVIDED	0	0.79622	0.656	0.971	GNOMAD_G_NFE	0.0070363074	GNOMAD_E_AMR=0.0030803352,GNOMAD_G_NFE=0.0070363074
8	11-1018093-G-GT_AR	MUC6	4588	AR	0.0096	0.7531	0.5030	0.9990	0.9989	1	0		rs376177791	11	1018093	1018093	G	GT	1	592.4500	PASS	0/1	frameshift_elongation	MUC6:ENST00000421673.2:c.4707dup:p.(Pro1570Thrfs*136)	UNCERTAIN_SIGNIFICANCE				NOT_PROVIDED	0	0.79622	0.656	0.971	GNOMAD_G_NFE	0.007835763	GNOMAD_G_NFE=0.007835763
```

--------------------------------

### Run Exomiser analysis with a Phenopacket

Source: https://exomiser.readthedocs.io/en/stable/input_files_and_options.html

Basic command to initiate an analysis using a Phenopacket file.

```bash
java -jar exomiser-cli-15.1.0.jar analyse --sample examples/pfeiffer-phenopacket.yml
```

--------------------------------

### Download Exomiser Program

Source: https://exomiser.readthedocs.io/en/stable/_sources/installation.rst.txt

Use wget to download the Exomiser distribution zip file on Linux or macOS.

```bash
# Download the Exomiser program (small, fast)
wget https://github.com/exomiser/Exomiser/releases/download/exomiser-cli-|version|-distribution.zip
```

--------------------------------

### Check Unzip Version

Source: https://exomiser.readthedocs.io/en/stable/_sources/installation.rst.txt

Verify if the installed unzip utility supports large files by checking for ZIP64_SUPPORT.

```bash
unzip -version
```

--------------------------------

### Run Exomiser with Custom Output Options

Source: https://exomiser.readthedocs.io/en/stable/input_files_and_options.html

Executes an analysis while applying a custom output configuration file.

```bash
java -jar exomiser-cli-15.1.0.jar analyse --sample examples/pfeiffer-phenopacket.yml --vcf path/to/manuel.vcf.gz --output path/to/output-options.yml
```

--------------------------------

### Run Exomiser Analysis with Sample and VCF

Source: https://exomiser.readthedocs.io/en/stable/input_files_and_options.html

Executes an analysis by providing a phenopacket sample and a VCF file with a specified genome assembly.

```bash
java -jar exomiser-cli-15.1.0.jar analyse --sample examples/pfeiffer-phenopacket.yml --vcf path/to/manuel.vcf.gz --assembly hg19
```

--------------------------------

### Define Data Directory Path

Source: https://exomiser.readthedocs.io/en/stable/installation.html

The target directory for extracted data files within the Exomiser installation folder.

```text
exomiser-cli-15.1.0/data
```

--------------------------------

### Configure Exomiser via Environment Variables

Source: https://exomiser.readthedocs.io/en/stable/_sources/installation.rst.txt

Set specific environment variables that correspond to properties in the application.properties file.

```bash
export EXOMISER_DATA_DIRECTORY=/full/path/to/exomiser-data
export EXOMISER_HG38_DATA_VERSION=2602
```

--------------------------------

### Run Analysis with VCF and Assembly

Source: https://exomiser.readthedocs.io/en/stable/_sources/input_files_and_options.rst.txt

Execute an analysis specifying a phenopacket sample, VCF file, and genome assembly.

```bash
java -jar exomiser-cli-|version|.jar analyse --sample examples/pfeiffer-phenopacket.yml --vcf path/to/manuel.vcf.gz --assembly hg19
```

--------------------------------

### Configure Data Directory Path

Source: https://exomiser.readthedocs.io/en/stable/installation.html

Sets the base path for Exomiser data files within the application.properties configuration file.

```properties
exomiser.data-directory=/data/exomiser-data
```

--------------------------------

### Run Exomiser Analysis

Source: https://exomiser.readthedocs.io/en/stable/_sources/input_files_and_options.rst.txt

Execute a standard Exomiser analysis using a YAML configuration file.

```bash
java -jar exomiser-cli-|version|.jar analyse --analysis examples/test-analysis-exome.yml
```

--------------------------------

### Configure Exomiser Output Options

Source: https://exomiser.readthedocs.io/en/stable/_sources/input_files_and_options.rst.txt

YAML configuration for controlling output directory, file naming, and formats.

```yaml
---
outputContributingVariantsOnly: false
# numGenes options: 0 = all or specify a limit e.g. 500 for the first 500 results
numGenes: 10
minExomiserGeneScore: 0.7
# outputDirectory: (optional) (default: '{exomiserDir}/results/')
outputDirectory: results/
# outputFileName: (optional) (default: 'input-vcf-name-exomiser')
	outputFileName: NA12345-exomiser-results
# out-format options: HTML, JSON, PARQUET, TSV_GENE, TSV_VARIANT, VCF (default: HTML)
outputFormats: [HTML, PARQUET]
```

--------------------------------

### VCF INFO Field Structure

Source: https://exomiser.readthedocs.io/en/stable/_sources/result_interpretation.rst.txt

Example of the Exomiser INFO field format within a VCF file, showing pipe-separated values for ranked alleles.

```text
##INFO=<ID=Exomiser,Number=.,Type=String,Description="A pipe-separated set of values for the proband allele(s) from the record with one per compatible MOI following the format: {RANK|ID|GENE_SYMBOL|ENTREZ_GENE_ID|MOI|P-VALUE|EXOMISER_GENE_COMBINED_SCORE|EXOMISER_GENE_PHENO_SCORE|EXOMISER_GENE_VARIANT_SCORE|EXOMISER_VARIANT_SCORE|CONTRIBUTING_VARIANT|WHITELIST_VARIANT|FUNCTIONAL_CLASS|HGVS|EXOMISER_ACMG_CLASSIFICATION|EXOMISER_ACMG_EVIDENCE|EXOMISER_ACMG_DISEASE_ID|EXOMISER_ACMG_DISEASE_NAME}">
#CHROM	POS	ID	REF	ALT	QUAL	FILTER	INFO	sample
10	123256215	.	T	G	100	PASS	Exomiser={1|10-123256215-T-G_AD|FGFR2|2263|AD|0.0000|0.9981|1.0000|1.0000|1.0000|1|1|missense_variant|FGFR2:ENST00000346997.2:c.1688A>C:p.(Glu563Ala)|LIKELY_PATHOGENIC|PM2&PP3_Strong&PP4&PP5|OMIM:123150|"Jackson-Weiss syndrome"};GENE=FGFR2;INHERITANCE=AD;MIM=101600	GT:DS:PL	1|0:2.000:50,11,0
11	1018088	.	TG	T	441.81	PASS	AC=1;AF=0.50;AN=2;BaseQRankSum=7.677;DP=162;DS;Exomiser={7|11-1018088-TG-T_AD|MUC6|4588|AD|0.0096|0.7532|0.5030|0.9990|0.9990|1|0|frameshift_variant|MUC6:ENST00000421673.2:c.4712del:p.(Pro1571Hisfs*21)|UNCERTAIN_SIGNIFICANCE|||""},{8|11-1018088-TG-T_AR|MUC6|4588|AR|0.0096|0.7531|0.5030|0.9990|0.9990|1|0|frameshift_variant|MUC6:ENST00000421673.2:c.4712del:p.(Pro1571Hisfs*21)|UNCERTAIN_SIGNIFICANCE|||""};FS=25.935;HRun=3;HaplotypeScore=1327.2952;MQ=43.58;MQ0=6;MQRankSum=-5.112;QD=2.31;ReadPosRankSum=2.472;set=variant	GT:AD:DP:GQ:PL	0/1:146,45:162:99:481,0,5488
11	1018093	.	G	GT	592.45	PASS	AC=1;AF=0.50;AN=2;BaseQRankSum=8.019;DP=157;Exomiser={7|11-1018093-G-GT_AD|MUC6|4588|AD|0.0096|0.7532|0.5030|0.9990|0.9989|0|0|frameshift_elongation|MUC6:ENST00000421673.2:c.4707dup:p.(Pro1570Thrfs*136)|NOT_AVAILABLE|||""},{8|11-1018093-G-GT_AR|MUC6|4588|AR|0.0096|0.7531|0.5030|0.9990|0.9989|1|0|frameshift_elongation|MUC6:ENST00000421673.2:c.4707dup:p.(Pro1570Thrfs*136)|UNCERTAIN_SIGNIFICANCE|||""};FS=28.574;HRun=1;HaplotypeScore=1267.6968;MQ=44.06;MQ0=4;MQRankSum=-5.166;QD=3.26;ReadPosRankSum=1.328;set=variant	GT:AD:DP:GQ:PL	0/1:140,42:157:99:631,0,4411
6	132203615	.	G	A	922.98	PASS	AC=1;AF=0.50;AN=2;BaseQRankSum=-0.671;DP=94;Dels=0.00;Exomiser={2|6-132203615-G-A_AD|ENPP1|5167|AD|0.0049|0.8690|0.5773|0.9996|0.9996|1|0|splice_donor_variant|ENPP1:ENST00000360971.2:c.2230+1G>A:p.?|UNCERTAIN_SIGNIFICANCE|PVS1_Strong|OMIM:615522|"Cole disease"};FS=0.805;HRun=0;HaplotypeScore=3.5646;MQ=56.63;MQ0=0;MQRankSum=1.807;QD=9.82;ReadPosRankSum=-0.900;set=variant2	GT:AD:DP:GQ:PL	0/1:53,41:94:99:953,0,1075
```

--------------------------------

### Run Analysis with Custom Output Options

Source: https://exomiser.readthedocs.io/en/stable/_sources/input_files_and_options.rst.txt

Execute an analysis while applying a custom output configuration file.

```bash
java -jar exomiser-cli-|version|.jar analyse --sample examples/pfeiffer-phenopacket.yml --vcf path/to/manuel.vcf.gz --output path/to/output-options.yml
```

--------------------------------

### Exomiser Home Directory Structure

Source: https://exomiser.readthedocs.io/en/stable/installation.html

Displays the directory structure created in the user's home directory upon the first execution of Exomiser.

```text
$ tree ~/.exomiser
/home/user/.exomiser
├── application.properties
└── data
```

--------------------------------

### Example ACMG variant report format

Source: https://exomiser.readthedocs.io/en/stable/_sources/acmg_assignment.rst.txt

Shows the structure of an ACMG assignment report for a variant, including the transcript, classification, criteria, and associated disease.

```text
1-12335-A-T, NC_000001.10:g.12335A>T, GENE1(ENST12345678):c.2346A>T:p.1234A>-, PATHOGENIC, [PVS1, PS1, PP4_Strong], Disease (OMIM:12345), AUTOSOMAL_DOMINANT
```

--------------------------------

### Structural Variant Gene Association Example

Source: https://exomiser.readthedocs.io/en/stable/_sources/sv_prioritisation.rst.txt

Illustrates how a single structural variant overlapping multiple genes is reported for each gene with its specific predicted effect.

```yaml
GENE1:
    variants:
        - 1-23456-78910-N-<DEL>
            variantEffect: TRANSCRIPT_ABLATION
GENE2:
    variants:
        - 1-23456-78910-N-<DEL>
            variantEffect: EXON_LOSS_VARIANT
```

--------------------------------

### Enable CADD in application.properties

Source: https://exomiser.readthedocs.io/en/stable/_sources/installation.rst.txt

Configure the CADD version and file paths in the application.properties file.

```text
cadd.version=1.4

exomiser.hg19.cadd-snv-path=${exomiser.data-directory}/cadd/${cadd.version}/hg19/whole_genome_SNVs.tsv.gz
exomiser.hg19.cadd-in-del-path=${exomiser.data-directory}/cadd/${cadd.version}/hg19/gnomad.genomes-exomes.r4.0.indel.tsv.gz

# and/or for hg38:
exomiser.hg38.cadd-snv-path=${exomiser.data-directory}/cadd/${cadd.version}/whole_genome_SNVs.tsv.gz
exomiser.hg38.cadd-in-del-path=${exomiser.data-directory}/cadd/${cadd.version}/gnomad.genomes.r4.0.indel.tsv.gz
```

--------------------------------

### Example Genes TSV Output

Source: https://exomiser.readthedocs.io/en/stable/_sources/result_interpretation.rst.txt

Sample content from a genes.tsv file showing how genes like MUC6 can appear multiple times under different MOI models.

```text
#RANK	ID	GENE_SYMBOL	ENTREZ_GENE_ID	MOI	P-VALUE	EXOMISER_GENE_COMBINED_SCORE	EXOMISER_GENE_PHENO_SCORE	EXOMISER_GENE_VARIANT_SCORE	HUMAN_PHENO_SCORE	MOUSE_PHENO_SCORE	FISH_PHENO_SCORE	WALKER_SCORE	PHIVE_ALL_SPECIES_SCORE	OMIM_SCORE	MATCHES_CANDIDATE_GENE	HUMAN_PHENO_EVIDENCE	MOUSE_PHENO_EVIDENCE	FISH_PHENO_EVIDENCE	HUMAN_PPI_EVIDENCE	MOUSE_PPI_EVIDENCE	FISH_PPI_EVIDENCE
1	FGFR2_AD	FGFR2	2263	AD	0.0000	0.9981	1.0000	1.0000	0.8808	1.0000	0.0000	0.5095	1.0000	1.0000	0	Jackson-Weiss syndrome (OMIM:123150): Brachydactyly (HP:0001156)-Broad hallux (HP:0010055), Craniosynostosis (HP:0001363)-Craniosynostosis (HP:0001363), Broad thumb (HP:0011304)-Broad metatarsal (HP:0001783), Broad hallux (HP:0010055)-Broad hallux (HP:0010055), 	Brachydactyly (HP:0001156)-abnormal sternum morphology (MP:0000157), Craniosynostosis (HP:0001363)-premature cranial suture closure (MP:0000081), Broad thumb (HP:0011304)-abnormal sternum morphology (MP:0000157), Broad hallux (HP:0010055)-abnormal sternum morphology (MP:0000157), 		Proximity to FGF14 associated with Spinocerebellar ataxia 27 (OMIM:609307): Broad hallux (HP:0010055)-Pes cavus (HP:0001761), 	Proximity to FGF14 Brachydactyly (HP:0001156)-abnormal digit morphology (MP:0002110), Broad thumb (HP:0011304)-abnormal digit morphology (MP:0002110), Broad hallux (HP:0010055)-abnormal digit morphology (MP:0002110),
2	ENPP1_AD	ENPP1	5167	AD	0.0049	0.8690	0.5773	0.9996	0.6972	0.5773	0.5237	0.5066	0.6972	1.0000	0	Autosomal recessive hypophosphatemic rickets (ORPHA:289176): Brachydactyly (HP:0001156)-Genu varum (HP:0002970), Craniosynostosis (HP:0001363)-Craniosynostosis (HP:0001363), Broad thumb (HP:0011304)-Tibial bowing (HP:0002982), Broad hallux (HP:0010055)-Genu varum (HP:0002970), 	Brachydactyly (HP:0001156)-fused carpal bones (MP:0008915), Craniosynostosis (HP:0001363)-abnormal nucleus pulposus morphology (MP:0006392), Broad thumb (HP:0011304)-fused carpal bones (MP:0008915), Broad hallux (HP:0010055)-fused carpal bones (MP:0008915), 	Craniosynostosis (HP:0001363)-ceratohyal cartilage premature perichondral ossification, abnormal (ZP:0012007), Broad thumb (HP:0011304)-cleithrum nodular, abnormal (ZP:0006782), 	Proximity to PAPSS2 associated with Brachyolmia 4 with mild epiphyseal and metaphyseal changes (OMIM:612847): Brachydactyly (HP:0001156)-Brachydactyly (HP:0001156), Broad thumb (HP:0011304)-Brachydactyly (HP:0001156), Broad hallux (HP:0010055)-Brachydactyly (HP:0001156), 	Proximity to PAPSS2 Brachydactyly (HP:0001156)-abnormal long bone epiphyseal plate morphology (MP:0003055), Craniosynostosis (HP:0001363)-domed cranium (MP:0000440), Broad thumb (HP:0011304)-abnormal long bone epiphyseal plate morphology (MP:0003055), Broad hallux (HP:0010055)-abnormal long bone epiphyseal plate morphology (MP:0003055),
//
7	MUC6_AD	MUC6	4588	AD	0.0096	0.7532	0.5030	0.9990	0.0000	0.0000	0.0000	0.5030	0.5030	1.0000	0						Proximity to GKN2 Brachydactyly (HP:0001156)-brachydactyly (MP:0002544), Broad thumb (HP:0011304)-brachydactyly (MP:0002544), Broad hallux (HP:0010055)-brachydactyly (MP:0002544),
8	MUC6_AR	MUC6	4588	AR	0.0096	0.7531	0.5030	0.9990	0.0000	0.0000	0.0000	0.5030	0.5030	1.0000	0						Proximity to GKN2 Brachydactyly (HP:0001156)-brachydactyly (MP:0002544), Broad thumb (HP:0011304)-brachydactyly (MP:0002544), Broad hallux (HP:0010055)-brachydactyly (MP:0002544),
```

--------------------------------

### Configure Data Directory

Source: https://exomiser.readthedocs.io/en/stable/_sources/installation.rst.txt

Settings for specifying the custom data directory path and verifying its structure.

```properties
exomiser.data-directory=/data/exomiser-data
```

```bash
/data/exomiser-data/
├── 2512_hg19
├── 2512_hg38
└── 2512_phenotype
```

```properties
exomiser.data-directory=/data/exomiser-data
exomiser.hg19.data-version=2512
exomiser.phenotype.data-version=2512
```

```properties
exomiser.data-directory=/data/exomiser-data
exomiser.hg38.data-version=2512
exomiser.phenotype.data-version=2512
```

```properties
exomiser.data-directory=/data/exomiser-data
exomiser.hg19.data-version=2512
exomiser.hg38.data-version=2512
exomiser.phenotype.data-version=2512
```

--------------------------------

### Run Exomiser with genome preset

Source: https://exomiser.readthedocs.io/en/stable/input_files_and_options.html

Use the genome preset for WGS samples; requires REMM score data configuration.

```bash
java -jar exomiser-cli-15.1.0.jar analyse --sample path/to/phenopacket.json --preset genome
```
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