<html><head><style>body{font-family:Helvetica,Arial;font-size:13px}</style></head><body style="word-wrap: break-word; -webkit-nbsp-mode: space; -webkit-line-break: after-white-space;"><div id="bloop_customfont" style="font-family:Helvetica,Arial;font-size:13px; color: rgba(0,0,0,1.0); margin: 0px; line-height: auto;">Hi Fergal,</div><div id="bloop_customfont" style="font-family:Helvetica,Arial;font-size:13px; color: rgba(0,0,0,1.0); margin: 0px; line-height: auto;"><br></div><div id="bloop_customfont" style="font-family:Helvetica,Arial;font-size:13px; color: rgba(0,0,0,1.0); margin: 0px; line-height: auto;">Thanks for the explanation and the files. This will help us debug any future issues.</div><div id="bloop_customfont" style="font-family:Helvetica,Arial;font-size:13px; color: rgba(0,0,0,1.0); margin: 0px; line-height: auto;"><br></div><div id="bloop_customfont" style="font-family:Helvetica,Arial;font-size:13px; color: rgba(0,0,0,1.0); margin: 0px; line-height: auto;">Regards,</div><div id="bloop_customfont" style="font-family:Helvetica,Arial;font-size:13px; color: rgba(0,0,0,1.0); margin: 0px; line-height: auto;">Vasisht</div> <div id="bloop_sign_1423152791659234048" class="bloop_sign"></div> <br><p style="color:#000;">On February 5, 2015 at 9:01:21 AM, Fergal (<a href="mailto:fergal@ebi.ac.uk">fergal@ebi.ac.uk</a>) wrote:</p> <blockquote type="cite" class="clean_bq"><span><div style="word-wrap: break-word; -webkit-nbsp-mode: space; -webkit-line-break: after-white-space;"><div></div><div>
<div>
<div>On 4 Feb 2015, at 14:53, Vasisht Tadigotla <<a href="mailto:vasisht.tadigotla@courtagen.com">vasisht.tadigotla@courtagen.com</a>>
wrote:</div>
<br class="Apple-interchange-newline">
<blockquote type="cite">
<div style="font-family: Helvetica, Arial; font-size: 13px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; orphans: auto; text-align: start; text-indent: 0px; text-transform: none; white-space: normal; widows: auto; word-spacing: 0px; -webkit-text-stroke-width: 0px; word-wrap: break-word; -webkit-nbsp-mode: space; -webkit-line-break: after-white-space;">
<div id="bloop_customfont" style="font-family: Helvetica, Arial; font-size: 13px; margin: 0px;">Hi
Will,</div>
<div id="bloop_customfont" style="font-family: Helvetica, Arial; font-size: 13px; margin: 0px;">
<br></div>
<div id="bloop_customfont" style="font-family: Helvetica, Arial; font-size: 13px; margin: 0px;">
Thanks for the clarification. Is there a list of transcripts where
the RefSeq sequence doesn’t match the reference?</div>
<div id="bloop_customfont" style="font-family: Helvetica, Arial; font-size: 13px; margin: 0px;">
<br></div>
<div id="bloop_customfont" style="font-family: Helvetica, Arial; font-size: 13px; margin: 0px;">
Regards,</div>
<div id="bloop_customfont" style="font-family: Helvetica, Arial; font-size: 13px; margin: 0px;">
Vasisht </div>
<div id="bloop_sign_1423061420679589888" class="bloop_sign"></div>
<br>
<p style="">On February 4, 2015 at 4:38:56 AM, Will McLaren
(<a href="mailto:wm2@ebi.ac.uk">wm2@ebi.ac.uk</a>) wrote:</p>
<blockquote type="cite" class="clean_bq">
<div dir="ltr"><span>Hi Vasisht,</span>
<div><span><br></span></div>
<div><span>Our RefSeq transcript set is imported from a file of
coordinates provided by NCBI. In some cases the sequence of a
RefSeq transcript does not match the reference sequence over which
it is mapped, which causes a problem since Ensembl does not import
the original RefSeq sequence, only the coordinates to which it
maps.</span></div>
<div><span><br></span></div>
<div><span>This means that retrieving and manipulating the sequence
in these transcripts can lead to misinterpretations, as is the case
here. According to our analysis there is a 1bp insertion in the
RefSeq sequence that does not appear in the reference; this would
explain the out by 1 error here.</span></div>
<div><span><br></span></div>
<div><span>We hope to be able to provide information about these
mismatches in the output from the next version of VEP. In the
meantime we would always recommend to use the Ensembl transcript
set where possible, as (among other good reasons!) transcript
sequences always match the underlying reference.</span></div>
<div><span><br></span></div>
<div><span>Regards</span></div>
<div><span><br></span></div>
<div><span>Will McLaren</span></div>
<div><span>Ensembl Variation</span></div>
</div>
<span><br>
On 3 February 2015 at 23:27, Vasisht Tadigotla <span dir="ltr"><<a href="mailto:vasisht.tadigotla@courtagen.com" target="_blank">vasisht.tadigotla@courtagen.com</a>></span> wrote:<br>
</span>
<div style="word-wrap: break-word;">
<div style="margin: 0px;"><font face="Helvetica">Hi,</font></div>
<div style="margin: 0px;"><font face="Helvetica"><br></font></div>
<div style="margin: 0px;"><font face="Helvetica">I’m annotating a
variant using GRCh37 and the VEP in the v78 release and the
HGVS annotation of the refseq transcripts doesn’t seem to match up
to the sequences for those transcripts.</font></div>
<div style="margin: 0px;"><font face="Helvetica"><br></font></div>
<div style="margin: 0px;"><font face="Helvetica">The variant is in
SLC37A4 (chr11:g.118895980CAG>C), the HGVS annotations
are NM_001467.5:c.1043_1044delCT
and NP_001458.1:p.Pro348ArgfsTer? and the amino acid is being
annotated as CCT/C. The aa change is the same for all refseq
transcripts in the annotation. </font></div>
<div style="margin: 0px;"><font face="Helvetica"><br></font></div>
<div style="margin: 0px;"><font face="Helvetica">The count seems to
be off by one - it’s a CTG/G change. The local sequence context is
GCC CTG TTT with the TG being deleted. </font></div>
<div style="margin: 0px;"><font face="Helvetica"><br></font></div>
<div style="margin: 0px;"><font face="Helvetica">The correct HGVS
description is NM_001467.5:c.1042_1043delCT and
the protein is <span style="color: rgb(51, 51, 51); line-height: 18px;">p.Leu348Valfs*53. This
is annotated correctly in the Ensembl transcripts
- </span>ENST00000545985.1:c.1042_1043delCT, ENSP00000475241.1:p.Leu348ValfsTer53. </font></div>
<div style="margin: 0px;"><font face="Helvetica"><br></font></div>
<div style="margin: 0px;"><font face="Helvetica">The following
options were used for the annotation:</font></div>
<div style="margin: 0px;"><font face="Helvetica"><br></font></div>
<div style="margin: 0px;">
—offline —everything —merged </div>
<div style="margin: 0px;"><br></div>
<div style="margin: 0px;">The same issue exists with the web
version of VEP:</div>
<div style="margin: 0px;"><br></div>
<div style="margin: 0px;"><a href="http://grch37.ensembl.org/Homo_sapiens/Tools/VEP/Results?db=core;tl=Ba08mzoDSO2008gG-584627" target="_blank">http://grch37.ensembl.org/Homo_sapiens/Tools/VEP/Results?db=core;tl=Ba08mzoDSO2008gG-584627</a></div>
<div style="margin: 0px;"><br></div>
<div style="margin: 0px;"><br></div>
<div style="margin: 0px;">Thanks,</div>
<div style="margin: 0px;">Vasisht</div>
<font face="Helvetica"><br></font></div>
<br>
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