<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,<div class=""><br class=""></div><div class="">Yep, that’s correct.</div><div class=""><br class=""></div><div class="">One thing to be aware of however is that our HGVS code shifts variants reported in repeated regions in the 3’ direction by default, while our CDS position is not shifted in such a way. This is the most common cause of CDS position and HGVSc position mismatch, although it can also be caused by these RefSeq alignment mismatches.</div><div class=""><br class=""></div><div class="">Kind Regards,</div><div class="">Andrew<br class=""><div><br class=""><blockquote type="cite" class=""><div class="">On 21 Jan 2020, at 11:08, Wallace Ko <<a href="mailto:myko@l3-bioinfo.com" class="">myko@l3-bioinfo.com</a>> wrote:</div><br class="Apple-interchange-newline"><div class=""><div dir="ltr" class="">Hi Andrew,<div class=""><br class=""></div><div class="">Thanks for the prompt response.</div><div class="">May I assume that this is just the problem of HGVS calculation and CDS position is already corrected by RefSeq alignment in such case?</div><div class=""><br clear="all" class=""><div class=""><div dir="ltr" class="gmail_signature" data-smartmail="gmail_signature"><div dir="ltr" class="">Regards,<div class="">Wallace Ko</div></div></div></div><br class=""></div></div><br class=""><div class="gmail_quote"><div dir="ltr" class="gmail_attr">On Tue, Jan 21, 2020 at 6:30 PM Andrew Parton <<a href="mailto:aparton@ebi.ac.uk" class="">aparton@ebi.ac.uk</a>> wrote:<br class=""></div><blockquote class="gmail_quote" style="margin:0px 0px 0px 0.8ex;border-left:1px solid rgb(204,204,204);padding-left:1ex"><div style="overflow-wrap: break-word;" class=""><div class=""><span class="">Hi Wallace,</span></div><span class=""><div class=""><span class=""><br class=""></span></div>Thanks for this report, it is an issue we are aware of. As you identified, not all RefSeq transcripts completely match the reference genome. In cases where they don't, we are now using alignment files provided by NCBI to create a new reference, matching the transcript, and use this for consequence calling.</span><div class=""><span class=""><br class=""></span><span class="">Our HGVS calculation does not currently use this reference modification, but it is something we are working on and aim to release later this year. VEP can report reference miss-matches for GRCh38, but these data are not available for GRCh37.</span></div><div class=""><span class=""><br class=""></span><span class="">More details on the differences to the reference genome and correcting transcript models using BAM can be found here: <a href="https://www.ensembl.org/info/docs/tools/vep/script/vep_other.html#refseq" target="_blank" class="">https://www.ensembl.org/info/docs/tools/vep/script/vep_other.html#refseq</a></span></div><div class=""><span class=""><br class=""></span><span class="">Let us know if there’s anything else we can do to help.</span></div><div class=""><span class=""><br class=""></span></div><div class=""><span class="">Kind Regards,</span></div><div class="">Andrew<br class=""><div class=""><span class=""><br class=""></span><div class=""><blockquote type="cite" class=""><div class="">On 21 Jan 2020, at 09:23, Wallace Ko <<a href="mailto:myko@l3-bioinfo.com" target="_blank" class="">myko@l3-bioinfo.com</a>> wrote:</div><br class=""><div class=""><div dir="ltr" class="">Hi Ensembl Developers,<div class=""><br class=""></div><div class="">The variant NC_000012.11:g.103249104C>A is annotated by online VEP and offline cached VEP (99, RefSeq, GRCh37) as:<br class=""></div><div class=""><ul class=""><li class="">HGVSc: NM_000277.1:<b class="">c.517</b>G>T</li><li class="">HGVSp: NP_000268.1:p.Gln172His<br class=""></li><li class="">CDS Position: 516</li></ul></div><div class="">On the other hand, <a href="https://www.ncbi.nlm.nih.gov/clinvar/variation/664621/" target="_blank" class="">ClinVar</a> reports the variant as NM_000277.3:<b class="">c.516</b>G>T (NP_000268.1:p.Gln172His). Besides, blast result shows that there is a 1-bp gap between c.303 and c.304 when NM_000277.1 is aligned to NC_000012.11. And even VEP itself reports the CDS position as 516.</div><div class=""><br class=""></div><div class="">All these make me believe that the HGVSc reported should be at c.516 instead of c.517.</div><div class=""><br clear="all" class=""><div class=""><div dir="ltr" class=""><div dir="ltr" class="">Regards,<div class="">Wallace Ko</div></div></div></div></div></div>
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