VEP and gnomAD AF inconsistencies
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Entering edit mode
17 months ago
cocchi.e89 ▴ 170

I found some inconsistencies between VEP annotated VCF gnomAD fields and gnomAD actual DB.

I am using VEP v98 on a Debian 9 machine. dbNSFP v4.0a.

As example, variant 12-116398626-A-C (here gnomAD page) is reported with a genome AF of 0.378 (37.8%).

If I isolate this variant only from VCF file:

chr12   116398626   .   A   C   584.19  PASS AC=2;AF=0.333;AN=6;BaseQRankSum=-1.007;ClippingRankSum=0;DP=42;ExcessHet=3.9794;FS=0;MLEAC=2;MLEAF=0.333;MQ=60;MQ0=0;MQRankSum=0;QD=17.7;ReadPosRankSum=-0.279;SOR=1.022 GT:AD:DP:GQ:PL    0/1:7,8:15:99:230,0,232 0/1:7,11:18:99:386,0,236    0/0:9,0:9:24:0,24,360

and pass it through VEP with both --af_gnomad and dbNSFP gnomAD AF flags:

/home/enrico/vep/ensembl-vep/vep -v \ -i "${sample_vcf_normalized}.ch12_116398626.vcf" --format vcf \ --cache --dir_cache /media/enrico/vep_disk/vep_files/ --merged --use_given_ref \ --fasta /media/enrico/vep_disk/vep_files/fasta/GRCh37/Homo_sapiens.GRCh37.75.dna.primary_assembly.fa.gz \ --dir_plugins /media/enrico/vep_disk/vep_files/Plugins/ \ --assembly GRCh37 \ --offline \ --minimal \ --vcf \ --hgvs \ --no_stats \ --symbol \ --allele_number \ --pick \ --no_intergenic \ --gencode_basic \ --sift b \ --polyphen b \ --plugin SingleLetterAA \ --plugin dbNSFP,/media/enrico/vep_disk/vep_files/plugin_databases/dbNSFP/dbNSFP4.0a.gz,LRT_score,LRT_pred,GERP++_RS,MutationTaster_pred,MutationTaster_score,MutationAssessor_pred,MutationAssessor_score,FATHMM_score,FATHMM_pred,1000Gp3_AC,1000Gp3_AF,1000Gp3_AFR_AC,1000Gp3_AFR_AF,1000Gp3_EUR_AC,1000Gp3_EUR_AF,1000Gp3_AMR_AC,1000Gp3_AMR_AF,1000Gp3_EAS_AC,1000Gp3_EAS_AF,1000Gp3_SAS_AC,1000Gp3_SAS_AF,UK10K_AF,ESP6500_AA_AF,ESP6500_EA_AF,gnomAD_exomes_POPMAX_AF,gnomAD_exomes_POPMAX_nhomalt,gnomAD_genomes_POPMAX_AF,gnomAD_genomes_POPMAX_nhomalt,GTEx_V7_gene,GTEx_V7_tissue,Geuvadis_eQTL_target_gene,Polyphen2_HDIV_score,Polyphen2_HDIV_pred,Polyphen2_HVAR_score,Polyphen2_HVAR_pred,ExAC_AC,ExAC_AF,ExAC_Adj_AF,ExAC_AFR_AC,ExAC_AFR_AF,ExAC_AMR_AC,ExAC_AMR_AF,ExAC_EAS_AC,ExAC_EAS_AF,ExAC_FIN_AC,ExAC_FIN_AF,ExAC_NFE_AC,ExAC_NFE_AF,ExAC_SAS_AC,ExAC_SAS_AF,REVEL_score,REVEL_rankscore,clinvar_id,clinvar_clnsig,clinvar_trait,clinvar_review,clinvar_hgvs,clinvar_var_source,clinvar_MedGen_id,clinvar_OMIM_id,clinvar_Orphanet_id,CADD_phred,ExAC_Adj_AC,gnomAD_exomes_AN,gnomAD_exomes_AC,gnomAD_genomes_AN,gnomAD_genomes_AC,gnomAD_exomes_controls_AC,gnomAD_exomes_controls_AN,gnomAD_exomes_AFR_AF,gnomAD_exomes_AMR_AF,gnomAD_exomes_ASJ_AF,gnomAD_exomes_EAS_AF,gnomAD_exomes_FIN_AF,gnomAD_exomes_NFE_AF,gnomAD_exomes_SAS_AF,gnomAD_exomes_controls_AF,gnomAD_genomes_controls_AC,gnomAD_genomes_controls_AN,gnomAD_genomes_AFR_AF,gnomAD_genomes_AMR_AF,gnomAD_genomes_ASJ_AF,gnomAD_genomes_EAS_AF,gnomAD_genomes_FIN_AF,gnomAD_genomes_NFE_AF,gnomAD_genomes_controls_AF,genename \ --custom /media/enrico/vep_disk/vep_files/manual_annotations/clinvar/clinvar_20191118.vcf.gz,ClinVar,vcf,exact,0,CLNSIG,CLNREVSTAT,CLNDN,CLNDISDB \ --force_overwrite \ --af_gnomad \ -o "${sample_vcf_normalized}.ch12_116398626.vep.vcf"

I got an empty fields for both, as the variant wouldn't be in gnomAD!

chr12   116398626   .   A   C   584.19  PASS    AC=2;AF=0.333;AN=6;BaseQRankSum=-1.007;ClippingRankSum=0;DP=42;ExcessHet=3.9794;FS=0;MLEAC=2;MLEAF=0.333;MQ=60;MQ0=0;MQRankSum=0;QD=17.7;ReadPosRankSum=-0.279;SOR=1.022;CSQ=C|3_prime_UTR_variant|MODIFIER|MED13L|ENSG00000123066|Transcript|ENST00000281928|protein_coding|31/31||ENST00000281928.3:c.*445T>G||7285|||||rs66898998|1||-1||1|HGNC|22962||Ensembl||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||   GT:AD:DP:GQ:PL  0/1:7,8:15:99:230,0,232 0/1:7,11:18:99:386,0,236    0/0:9,0:9:24:0,24,360

Does anybody knows why??

Thank you in advance for any help!

vep ensembl gnomad AF dbNSFP • 684 views
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Entering edit mode
17 months ago
Ben_Ensembl ★ 1.8k

Hi cocchi.e89,

By default the VEP only reports allele frequencies from the gnomAD exomes dataset. However, you can configure the VEP to retrieve allele frequencies from the gnomAD genomes dataset via VEP's custom annotation functionality: http://www.ensembl.org/info/docs/tools/vep/script/vep_example.html#gnomad

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