yup, quick check with bcftools norm seems to make the vcfs the same
Why do these two variants appear to result in the same amino acid change when annotated by snpeff, but are annotated differently in clinvar
I am running the following command for two vcfs, each containing one variant
snpEff -Xmx64G 'hg38' my_vcf | SnpSift annotate -noId clinvar.vcf.gz
This is the result of vcf1
13 32354919 rs397507894 TTT T . . AF=2.52525e-05;MAF=2.52525e-05;;ANN=T|frameshift_variant|HIGH|BRCA2|BRCA2|transcript|NM_000059.3|protein_coding|14/27|c.7067_7068delTT|p.Phe2356fs|7294/11386|7067/10257|2356/3418||;LOF=(BRCA2|BRCA2|1|1.00)
Here is the result of vcf2:
13 32354918 52262 ATT A . . ANN=A|frameshift_variant|HIGH|BRCA2|BRCA2|transcript|NM_000059.3|protein_coding|14/27|c.7067_7068delTT|p.Phe2356fs|7294/11386|7067/10257|2356/3418||INFO_REALIGN_3_PRIME;LOF=(BRCA2|BRCA2|1|1.00);ALLELEID=66930;CLNDISDB=MONDO:MONDO:0012933,MedGen:C2675520,OMIM:612555,Orphanet:145|MONDO:MONDO:0016419,MedGen:C0346153,OMIM:114480,Orphanet:227535;CLNDN=Breast-ovarian_cancer,_familial,_susceptibility_to,_2|Familial_cancer_of_breast;CLNHGVS=NC_000013.11:g.32354920_32354921del;CLNREVSTAT=reviewed_by_expert_panel;CLNSIG=Pathogenic;CLNVC=Deletion;CLNVCSO=SO:0000159;CLNVI=ClinGen:CA024828;GENEINFO=BRCA2:675;MC=SO:0001589|frameshift_variant;ORIGIN=1;RS=397507894
It seems like both of these result in the same change NM_000059.3:c.7067_7068delTT and p.Phe2356fs, but one is annotated in Clinvar as pathogenic and the other one isnt? Why is this?
I can see the Clinvar VCF is like this:
13 32354918 52262 ATT A . . ALLELEID=66930;CLNDISDB=MONDO:MONDO:0012933,MedGen:C2675520,OMIM:612555,Orphanet:145|MONDO:MONDO:0016419,MedGen:C0346153,OMIM:114480,Orphanet:227535;CLNDN=Breast-ovarian_cancer,_familial,_susceptibility_to,_2|Familial_cancer_of_breast;CLNHGVS=NC_000013.11:g.32354920_32354921del;CLNREVSTAT=reviewed_by_expert_panel;CLNSIG=Pathogenic;CLNVC=Deletion;CLNVCSO=SO:0000159;CLNVI=ClinGen:CA024828;GENEINFO=BRCA2:675;MC=SO:0001589|frameshift_variant;ORIGIN=1;RS=397507894
Is the issue that SnpSift is niave to the protein change and just adds the annotation to vcf2 because the chrom:pos:ref:alt aligns perfectly with Clinvar?
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I think you need to normalize (left-align your VCFs before annotating): https://genome.sph.umich.edu/wiki/Variant_Normalization
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