Incidental findings using GEMINI

The American College of Medical Genetics and Genomics (ACMG) have recommended that genetic variants that may be pathogenic or likely pathogenic in certain genes should be reported back to the patient. The latest list of genes can be found here. How do I assess whether a variant is pathogenic or likely pathogenic? Use this tool, which follows the recommendations of ACMG.

We can use GEMINI to find variants that may be pathogenic by creating a query that returns variants that are in the list of 58 genes and have some evidence of being pathogenic or likely pathogenic based on the ClinVar database. I have created a GEMINI database using the gnomAD exome variants (gnomad.exomes.r2.0.1.sites.vcf.gz) and will use it as an example.

# how many variants?
gemini query -q 'select count(*) from variants' *.db
17009588

gemini query --header -q 'select chrom, start, end, ref, alt, gene, clinvar_sig, clinvar_disease_name, clinvar_dbsource, clinvar_dbsource_id, clinvar_origin, clinvar_dsdb, clinvar_dsdbid, clinvar_disease_acc, clinvar_in_locus_spec_db, clinvar_on_diag_assay, clinvar_causal_allele from variants where (gene == "ACTA2" OR gene == "ACTC1" OR gene == "APC" OR gene == "APOB" OR gene == "ATP7B" OR gene == "BMPR1A" OR gene == "BRCA1" OR gene == "BRCA2" OR gene == "CACNA1S" OR gene == "COL3A1" OR gene == "DSG2" OR gene == "DSP" OR gene == "FBN1" OR gene == "GLA" OR gene == "KCNH2" OR gene == "KCNQ1" OR gene == "LDLR" OR gene == "LMNA" OR gene == "MEN1" OR gene == "MLH1" OR gene == "MSH2" OR gene == "MSH6" OR gene == "MUTYH" OR gene == "MYBPC3" OR gene == "MYH11" OR gene == "MYH7" OR gene == "MYL2" OR gene == "MYL3" OR gene == "NF2" OR gene == "OTC" OR gene == "PCSK9" OR gene == "PKP2" OR gene == "PMS2" OR gene == "PRKAG2" OR gene == "PTEN" OR gene == "RB1" OR gene == "RET" OR gene == "RYR1" OR gene == "RYR2" OR gene == "SCN5A" OR gene == "SDHAF2" OR gene == "SDHB" OR gene == "SDHC" OR gene == "SDHD" OR gene == "SMAD3" OR gene == "SMAD4" OR gene == "STK11" OR gene == "TGFBR1" OR gene == "TGFBR2" OR gene == "TMEM43" OR gene == "TNNI3" OR gene == "TNNT2" OR gene == "TP53" OR gene == "TPM1" OR gene == "TSC1" OR gene == "TSC2" OR gene == "VHL" OR gene == "WT1" ) and clinvar_sig like "%pathogenic%" and clinvar_causal_allele == alt' *.db | head
chrom   start   end     ref     alt     gene    clinvar_sig     clinvar_disease_name    clinvar_dbsource        clinvar_dbsource_id     clinvar_origin  clinvar_dsdb    clinvar_dsdbid  clinvar_disease_acc     clinvar_in_locus_spec_db        clinvar_on_diag_assay   clinvar_causal_allele
chr10   90701550        90701551        G       A       ACTA2   pathogenic      Aortic_aneurysm,_familial_thoracic_6|Thoracic_aortic_aneurysm_and_aortic_dissection     OMIM_Allelic_Variant|UniProtKB_(protein)        102620.0001|P62736#VAR_045918   germline        MedGen:OMIM|MedGen:Orphanet     C2673186:611788|CN118826:ORPHA91387     RCV000019938.27|RCV000246692.1  1       0       A
chr10   90703569        90703570        C       T       ACTA2   pathogenic,likely-pathogenic    not_provided|Aortic_aneurysm,_familial_thoracic_6       UniProtKB_(protein)     P62736#VAR_045916       germline        MedGen|MedGen:OMIM      CN221809|C2673186:611788       RCV000181019.2|RCV000234479.1    0       0       T
chr15   35082634        35082635        A       G       ACTC1   uncertain,likely-pathogenic     not_provided|Cardiovascular_phenotype   .       .       germline        MedGen|MedGen   CN221809|CN230736       RCV000157802.1|RCV000245634.1   1       0       G
chr15   35083363        35083364        C       T       ACTC1   pathogenic      Dilated_cardiomyopathy_1R       OMIM_Allelic_Variant|UniProtKB_(protein)        102540.0001|P68032#VAR_012860   germline        MedGen:OMIM     C3150681:613424 RCV000019988.26 1       0      T
chr15   35085598        35085599        C       T       ACTC1   pathogenic,other        Familial_hypertrophic_cardiomyopathy_11|Left_ventricular_noncompaction_4|Primary_familial_hypertrophic_cardiomyopathy|not_provided      OMIM_Allelic_Variant|UniProtKB_(protein)       102540.0009|P68032#VAR_012857    germline        MedGen:OMIM|MedGen|MedGen:Orphanet:SNOMED_CT|MedGen     C2677506:612098|C3150682|C0949658:ORPHA155:83978005|CN221809    RCV000019996.31|RCV000019997.27|RCV000029295.3|RCV000157780.3   1       0       T
chr15   35085618        35085619        T       C       ACTC1   likely-pathogenic       Familial_hypertrophic_cardiomyopathy_11 .       .       germline        MedGen:OMIM     C2677506:612098 RCV000201495.1  0       0       C
chr15   35085631        35085632        G       A       ACTC1   uncertain,pathogenic    Familial_hypertrophic_cardiomyopathy_11|not_specified   OMIM_Allelic_Variant|UniProtKB_(protein)        102540.0004|P68032#VAR_045924   germline        MedGen:OMIM|MedGen      C2677506:612098|CN169374        RCV000019991.28|RCV000038323.3  1       0       A
chr5    112090656       112090657       C       T       APC     pathogenic,other        Hereditary_cancer-predisposing_syndrome|Familial_adenomatous_polyposis_1        .       .       germline        MedGen:SNOMED_CT|MedGen:OMIM    C0027672:699346009|C2713442:175100     RCV000164002.2|RCV000227124.1    1       0       T
chr5    112102883       112102884       A       G       APC     pathogenic      Hereditary_cancer-predisposing_syndrome .       .       germline        MedGen:SNOMED_CT        C0027672:699346009      RCV000163246.2  1       0       G

gemini query --header -q 'select chrom, start, end, ref, alt, gene, clinvar_sig, clinvar_disease_name, clinvar_dbsource, clinvar_dbsource_id, clinvar_origin, clinvar_dsdb, clinvar_dsdbid, clinvar_disease_acc, clinvar_in_locus_spec_db, clinvar_on_diag_assay, clinvar_causal_allele from variants where (gene == "ACTA2" OR gene == "ACTC1" OR gene == "APC" OR gene == "APOB" OR gene == "ATP7B" OR gene == "BMPR1A" OR gene == "BRCA1" OR gene == "BRCA2" OR gene == "CACNA1S" OR gene == "COL3A1" OR gene == "DSG2" OR gene == "DSP" OR gene == "FBN1" OR gene == "GLA" OR gene == "KCNH2" OR gene == "KCNQ1" OR gene == "LDLR" OR gene == "LMNA" OR gene == "MEN1" OR gene == "MLH1" OR gene == "MSH2" OR gene == "MSH6" OR gene == "MUTYH" OR gene == "MYBPC3" OR gene == "MYH11" OR gene == "MYH7" OR gene == "MYL2" OR gene == "MYL3" OR gene == "NF2" OR gene == "OTC" OR gene == "PCSK9" OR gene == "PKP2" OR gene == "PMS2" OR gene == "PRKAG2" OR gene == "PTEN" OR gene == "RB1" OR gene == "RET" OR gene == "RYR1" OR gene == "RYR2" OR gene == "SCN5A" OR gene == "SDHAF2" OR gene == "SDHB" OR gene == "SDHC" OR gene == "SDHD" OR gene == "SMAD3" OR gene == "SMAD4" OR gene == "STK11" OR gene == "TGFBR1" OR gene == "TGFBR2" OR gene == "TMEM43" OR gene == "TNNI3" OR gene == "TNNT2" OR gene == "TP53" OR gene == "TPM1" OR gene == "TSC1" OR gene == "TSC2" OR gene == "VHL" OR gene == "WT1" ) and clinvar_sig like "%pathogenic%" and clinvar_causal_allele == alt' *.db | wc -l
1623

Obviously you'll have to consider the inheritance model of the disorder, the evidence for pathogenicity, genotype quality, etc. The query above may find possible incidental findings. The list of genes will likely be changed in the future, so I wrote a script that can generate the above query based on a text file with a list of genes. I have shared incidental_finding.tsv here.

head incidental_finding.tsv 
ACTA2
ACTC1
APC
APOB
ATP7B
BMPR1A
BRCA1
BRCA2
CACNA1S
COL3A1

create_query.pl incidental_finding.tsv 
gemini query --header -q 'select chrom, start, end, ref, alt, gene, clinvar_sig, clinvar_disease_name, clinvar_dbsource, clinvar_dbsource_id, clinvar_origin, clinvar_dsdb, clinvar_dsdbid, clinvar_disease_acc, clinvar_in_locus_spec_db, clinvar_on_diag_assay, clinvar_causal_allele from variants where (gene == "ACTA2" OR gene == "ACTC1" OR gene == "APC" OR gene == "APOB" OR gene == "ATP7B" OR gene == "BMPR1A" OR gene == "BRCA1" OR gene == "BRCA2" OR gene == "CACNA1S" OR gene == "COL3A1" OR gene == "DSG2" OR gene == "DSP" OR gene == "FBN1" OR gene == "GLA" OR gene == "KCNH2" OR gene == "KCNQ1" OR gene == "LDLR" OR gene == "LMNA" OR gene == "MEN1" OR gene == "MLH1" OR gene == "MSH2" OR gene == "MSH6" OR gene == "MUTYH" OR gene == "MYBPC3" OR gene == "MYH11" OR gene == "MYH7" OR gene == "MYL2" OR gene == "MYL3" OR gene == "NF2" OR gene == "OTC" OR gene == "PCSK9" OR gene == "PKP2" OR gene == "PMS2" OR gene == "PRKAG2" OR gene == "PTEN" OR gene == "RB1" OR gene == "RET" OR gene == "RYR1" OR gene == "RYR2" OR gene == "SCN5A" OR gene == "SDHAF2" OR gene == "SDHB" OR gene == "SDHC" OR gene == "SDHD" OR gene == "SMAD3" OR gene == "SMAD4" OR gene == "STK11" OR gene == "TGFBR1" OR gene == "TGFBR2" OR gene == "TMEM43" OR gene == "TNNI3" OR gene == "TNNT2" OR gene == "TP53" OR gene == "TPM1" OR gene == "TSC1" OR gene == "TSC2" OR gene == "VHL" OR gene == "WT1" ) and clinvar_sig like "%pathogenic%" and clinvar_causal_allele == alt' *.db

And the script.

#!/usr/bin/env perl

use strict;
use warnings;

my $usage = "Usage: $0 <gene_list.txt>\n";
my $infile = shift or die $usage;

my $query = "gemini query --header -q 'select chrom, start, end, ref, alt, gene, clinvar_sig, clinvar_disease_name, clinvar_dbsource, clinvar_dbsource_id, clinvar_origin, clinvar_dsdb, clinvar_dsdbid, clinvar_disease_acc, clinvar_in_locus_spec_db, clinvar_on_diag_assay, clinvar_causal_allele from variants where (";

open(IN, '<', $infile) || die "Could not open $infile: $!\n";
while(<IN>){
   chomp;
   $query .= "gene == \"$_\" OR ";
}
close(IN);

$query =~ s/OR\s$/) and clinvar_sig like "%pathogenic%" and clinvar_causal_allele == alt' *.db/;
print "$query\n";
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