Depending on the output options provided, Exomiser will write out at least an HTML results file in the results sub-directory of the Exomiser installation.
As a general rule all output files contain a ranked list of genes and/or variants with the top-ranked gene/variant displayed first. The exception being the VCF output which, since version 13.1.0, is sorted according to VCF convention and tabix indexed.
Exomiser attempts to predict the variant or variants likely to be causative of a patient's phenotype and does so by associating them with the gene (or genes in the case of large structural variations) they intersect with on the genomic sequence. Variants occurring in intergenic regions are associated to the closest gene and those overlapping two genes are associated with the gene in which they are predicted to have the largest consequence.
Once associated with a gene, Exomiser uses the compatible modes of inheritance for a variant to assess it in the context of any diseases associated with the gene or any mouse knockout models of that gene. These are all bundled together into a GeneScore which features filtered variants located in that gene compatible with a given mode of inheritance. After the filtering steps Exomiser ranks these GeneScores according to descending combined score. The results are then written out to the files and formats specified in the output settings.
As of release 13.2.0 the output files only feature a single, combined output file of ranked genes/variants e.g. when supplying the output options (via an output-options.yaml file) outputFileName: Pfeiffer-hiphive-exome-PASS_ONLY and outputFormats: [TSV_VARIANT, TSV_GENE, VCF], the following files will be written out: Pfeiffer-hiphive-exome-PASS_ONLY.variants.tsv Pfeiffer-hiphive-exome-PASS_ONLY.genes.tsv, Pfeiffer-hiphive-exome-PASS_ONLY.vcf
These formats are detailed below.
The JSON file represents the most accurate representation of the data, as it is referenced internally by Exomiser. As such, we don't provide a schema for this, but it has been pretty stable and breaking changes will only occur with major version changes to the software. Minor additions are to be expected for minor releases, as per the SemVer specification.
We recommend using Python or JQ to extract data from this file.
In the genes.tsv file it is possible for a gene to appear multiple times, depending on the MOI it is compatible with, given the filtered variants. For example in the example below MUC6 is ranked 7th under the AD model and 8th under an AR model.
#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),In the variants.tsv file it is possible for a variant, like a gene, to appear multiple times, depending on the MOI it is compatible with. For example in the example below MUC6 has two variants ranked 7th under the AD model and two ranked 8th under an AR (compound heterozygous) model. In the AD case the CONTRIBUTING_VARIANT column indicates whether the variant was (1) or wasn't (0) used for calculating the EXOMISER_GENE_COMBINED_SCORE and EXOMISER_GENE_VARIANT_SCORE.
#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_ALLELE_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=0.007835763In the VCF file it is possible for a variant, like a gene, to appear multiple times, depending on the MOI it is compatible with. For example in the example below MUC6 has two variants ranked 7th under the AD model and two ranked 8th under an AR (compound heterozygous) model. In the AD case the CONTRIBUTING_VARIANT column indicates whether the variant was (1) or wasn't (0) used for calculating the EXOMISER_GENE_COMBINED_SCORE and EXOMISER_GENE_VARIANT_SCORE. The INFO field with the ID=Exomiser describes the internal format of this sub-field. Be aware that for multi-allelic sites, Exomiser will decompose and trim them for the proband sample and this is what will be displayed in the Exomiser ID sub-field e.g. 11-1018088-TG-T_AD.
##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 0/1:53,41:94:99:953,0,1075The VCF file is tabix-indexed and exomiser ranked alleles can be extracted using grep. For example, to display the top 5 ranked variants, you would issue the command:
zgrep -E '\{[1-5]{1}\|' Pfeiffer-hiphive-exome-PASS_ONLY.vcf.gz