<html><head><meta http-equiv="Content-Type" content="text/html; charset=utf-8"></head><body style="word-wrap: break-word; -webkit-nbsp-mode: space; line-break: after-white-space;" class="">Hi Will,<div class=""><br class=""></div><div class="">Thanks for this report, and good to hear from you. We have a solution for this that will be coming out in release 97. The flag —clin_sig_allele will be introduced which will alter the CLIN_SIG output to be allele specific.</div><div class=""><br class=""></div><div class="">Kind Regards,</div><div class="">Andrew</div><div class=""><br class=""><div><br class=""><blockquote type="cite" class=""><div class="">On 21 Jun 2019, at 11:07, Will McLaren <<a href="mailto:will.mclaren@globalgenecorp.com" class="">will.mclaren@globalgenecorp.com</a>> wrote:</div><br class="Apple-interchange-newline"><div class=""><div dir="ltr" class="">Hi list,<div class=""><br class=""></div><div class="">VEP reports clinical significance states for known variants in the CLIN_SIG field. There is potential for these to be mis-assigned to input variants due to the way the data are mapped and stored in Ensembl's database. This is best illustrated by example:</div><div class=""><br class=""></div><div class="">rs2228671 (<a href="http://www.ensembl.org/Homo_sapiens/Variation/Explore?r=19:11099736-11100736;v=rs2228671;vdb=variation;vf=142322991" class="">http://www.ensembl.org/Homo_sapiens/Variation/Explore?v=rs2228671</a>) is a SNV listed with four alleles (C/A/G/T). It has five ClinVar annotations mapped to it (<a href="http://www.ensembl.org/Homo_sapiens/Variation/Explore?r=19:11099736-11100736;v=rs2228671;vdb=variation;vf=142322991" class="">http://www.ensembl.org/Homo_sapiens/Variation/Phenotype?v=rs2228671</a>), with varying significance states. If your input to VEP matches any of the three ALT alleles (A, G, or T) at this position, then the returned CLIN_SIG field is a list of all of those states, since the ClinVar entries are assigned at the variant level (rsID), rather than more precisely at the allele level. Post-filtering your VEP results for pathogenic variants will then match, regardless of whether your input ALT was a pathogenic (T) or benign (A) allele at this position.</div><div class=""><br class=""></div><div class="">A good solution is to use VEP's custom annotation function along with the VCF files made available by ClinVar (<a href="https://www.ncbi.nlm.nih.gov/variation/docs/ClinVar_vcf_files/" class="">https://www.ncbi.nlm.nih.gov/variation/docs/ClinVar_vcf_files/</a>), something like:</div><div class=""><br class=""></div><div class="">vep [options] -custom clinvar_20190609.vcf.gz,clinvar,vcf,exact,,CLNSIG</div><div class=""><br class=""></div><div class="">which will give correct allele-specific clinical significance states in the clinvar_CLNSIG field of the VEP output.</div><div class=""><br class=""></div><div class="">I haven't reported this as a bug for VEP as really it's a bug in the way Ensembl stores the data.</div><div class=""><br class=""></div><div class="">Cheers</div><div class=""><br class=""></div><div class="">Will</div><div class=""><br class=""></div><div class="">## commands to reproduce:</div><div class=""><br class=""></div><div class=""># the A allele is pathogenic</div><div class="">$ vep -id "19 11100236 test1 C A" -cache -o stdout -no_head -pick -tab -check_ex -fields CLIN_SIG,clinvar_CLNSIG -custom clinvar_20190609.vcf.gz,clinvar,vcf,exact,,CLNSIG</div><div class="">benign,pathogenic Pathogenic</div><div class=""><br class=""></div><div class=""># the T allele is benign</div><div class="">$ vep -id "19 11100236 test1 C T" -cache -o stdout -no_head -pick -tab -check_ex -fields CLIN_SIG,clinvar_CLNSIG -custom clinvar_20190609.vcf.gz,clinvar,vcf,exact,,CLNSIG</div><div class="">benign,pathogenic Benign/Likely_benign<br class=""></div><div class=""><div class=""><br class=""></div>-- <br class=""><div dir="ltr" class="gmail_signature" data-smartmail="gmail_signature"><div dir="ltr" class=""><div class=""><div dir="ltr" class="">-- <br class=""><span style="font-size:12.8px" class=""><b class="">William McLaren</b></span><br style="font-size:12.8px" class=""><span style="font-size:12.8px" class="">Senior Bioinformatics Scientist</span><br style="font-size:12.8px" class=""><span style="font-size:12.8px" class="">Global Gene Corp</span><br style="font-size:12.8px" class=""><a href="mailto:will.mclaren@globalgenecorp.com" style="color:rgb(17,85,204);font-size:12.8px" target="_blank" class="">will.mclaren@globalgenecorp.com</a><br style="font-size:12.8px" class=""><a href="https://www.globalgenecorp.com/" style="color:rgb(17,85,204);font-size:12.8px" target="_blank" class="">www.globalgenecorp.com</a><br style="font-size:12.8px" class=""><span style="font-size:12.8px" class="">The BIC, Wellcome Genome Campus, Hinxton, Cambridge CB10 1DR</span></div></div></div></div></div></div>
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