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<p>Hi Michael,</p>
<p>Apologies for the delay in getting back to you. <br>
</p>
<p>This does look like problem caused by the miss-match between the
reference genome sequence and the transcript. We currently use
NCBI's alignments to 'correct' the underlying reference to match
the transcript sequence and use this in consequence calling and
codon derivation, which is why the codons here are reported as '<b>C</b>GG/<b>C</b>GG'.
We are currently updating our HGVS writing code to also use this
'corrected' sequence.<br>
</p>
<p>We take transcript mapping information from NCBI, which is why we
report the position as 1027, in agreement with dbSNP. Where are
you seeing the mapping to 1099?</p>
<p>Best wishes,</p>
<p>Sarah<br>
<span
style="font-family:Calibri,Helvetica,sans-serif,EmojiFont,"Apple
Color Emoji","Segoe UI
Emoji",NotoColorEmoji,"Segoe UI
Symbol","Android Emoji",EmojiSymbols"></span></p>
<p><br>
</p>
<div class="moz-cite-prefix">On 24/10/2018 20:32, Michael Yourshaw
wrote:<br>
</div>
<blockquote type="cite"
cite="mid:CANcs_J+_oLLzY-gQo3SOU8w0UnDPVsjGonLt7i8satsH67_C2g@mail.gmail.com">
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<p
style="margin-top:0px;margin-bottom:0px;color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px">This
question relates to VEP 93 Human.</p>
<p
style="margin-top:0px;margin-bottom:0px;color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px"><br>
</p>
<p
style="margin-top:0px;margin-bottom:0px;color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px">I've
seen a few cases where the hgvsc computed by VEP seems to be
wrong. </p>
<p
style="margin-top:0px;margin-bottom:0px;color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px">for
example the genomic variant chr1:942451T>C
(rs6672356) for the canonical transcripts produces these
hgvsc values in VEP:</p>
<p
style="margin-top:0px;margin-bottom:0px;color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px">
- 'ENST00000342066.7:c.1027T>C'</p>
<p
style="margin-top:0px;margin-bottom:0px;color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px">
- 'NM_152486.2:c.1027T>C'</p>
<p
style="margin-top:0px;margin-bottom:0px;color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px"><br>
</p>
<p
style="margin-top:0px;margin-bottom:0px;color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px"><span
style="font-family:Calibri,Helvetica,sans-serif,EmojiFont,"Apple
Color Emoji","Segoe UI
Emoji",NotoColorEmoji,"Segoe UI
Symbol","Android Emoji",EmojiSymbols">Looking
at the cDNA sequence, the reference for NM_152486.2:c.1027</span> is
not T but C.</p>
<p
style="margin-top:0px;margin-bottom:0px;color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px"><br>
</p>
<p
style="margin-top:0px;margin-bottom:0px;color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px">As
best I can tell, <span
style="font-family:Calibri,Helvetica,sans-serif,EmojiFont,"Apple
Color Emoji","Segoe UI
Emoji",NotoColorEmoji,"Segoe UI
Symbol","Android Emoji",EmojiSymbols">chr1:942451
does not map to cDNA NM_152486.2 at 1027, but rather to
1099, which contains the expected T as a reference.</span></p>
<p
style="margin-top:0px;margin-bottom:0px;color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px"><span
style="font-family:Calibri,Helvetica,sans-serif,EmojiFont,"Apple
Color Emoji","Segoe UI
Emoji",NotoColorEmoji,"Segoe UI
Symbol","Android Emoji",EmojiSymbols"><br>
</span></p>
<p
style="margin-top:0px;margin-bottom:0px;color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px"><span
style="font-family:Calibri,Helvetica,sans-serif,EmojiFont,"Apple
Color Emoji","Segoe UI
Emoji",NotoColorEmoji,"Segoe UI
Symbol","Android Emoji",EmojiSymbols">The
Alamut annotator for this variant fails with the reason
"Transcript NM_152486.2: Genome/Transcript discrepancy:
Alternate genomic nucleotide (C) same as transcript
nucleotide (Assembly: GRCh38)"</span></p>
<p
style="margin-top:0px;margin-bottom:0px;color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px"><br>
</p>
<p
style="margin-top:0px;margin-bottom:0px;color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px">dbSNP
for <span
style="font-family:Calibri,Helvetica,sans-serif,EmojiFont,"Apple
Color Emoji","Segoe UI
Emoji",NotoColorEmoji,"Segoe UI
Symbol","Android Emoji",EmojiSymbols">rs6672356
contains</span><br>
</p>
<p
style="margin-top:0px;margin-bottom:0px;color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px"><span
style="font-family:Calibri,Helvetica,sans-serif,EmojiFont,"Apple
Color Emoji","Segoe UI
Emoji",NotoColorEmoji,"Segoe UI
Symbol","Android Emoji",EmojiSymbols"></span></p>
<div
style="color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px">
NM_152486.2:c.1027C=</div>
<div
style="color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px">
NM_152486.2:c.1027C>T</div>
<p
style="margin-top:0px;margin-bottom:0px;color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px"><span
style="font-family:Calibri,Helvetica,sans-serif,EmojiFont,"Apple
Color Emoji","Segoe UI
Emoji",NotoColorEmoji,"Segoe UI
Symbol","Android Emoji",EmojiSymbols"><br>
</span></p>
<p
style="margin-top:0px;margin-bottom:0px;color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px"><span
style="font-family:Calibri,Helvetica,sans-serif,EmojiFont,"Apple
Color Emoji","Segoe UI
Emoji",NotoColorEmoji,"Segoe UI
Symbol","Android Emoji",EmojiSymbols">This
particular issue has a discussion in BioStars (<a
href="https://www.biostars.org/p/239892/"
target="_blank" rel="noopener noreferrer"
class="gmail-x_OWAAutoLink" id="gmail-LPlnk632316"
moz-do-not-send="true">https://www.biostars.org/p/239892/</a>).
But I do not think the explanation suggested
there applies: that it is just a difference between RefSeq
and the reference genome.</span></p>
<p
style="margin-top:0px;margin-bottom:0px;color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px"><br>
</p>
<p
style="margin-top:0px;margin-bottom:0px;color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px">These
variants also seem to have a similar problem:</p>
<div
style="color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px">rs10902758
NC_000004.12:g.654854G>A NM_000283.3:c.958G>A</div>
<div
style="color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px">***
NM_000283.3:c.958G>A: Variant reference (G) does not
agree with reference sequence (A)</div>
<div
style="color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px">rs10902758
NC_000004.12:g.654854G>A NM_001145291.1:c.958G>A</div>
<div
style="color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px">***
NM_001145291.1:c.958G>A: Variant reference (G) does not
agree with reference sequence (A)</div>
<div
style="color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px">rs10902758
NC_000004.12:g.654854G>A NM_001145292.1:c.121G>A</div>
<div
style="color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px">***
NM_001145292.1:c.121G>A: Variant reference (G) does not
agree with reference sequence (A)</div>
<div
style="color:rgb(0,0,0);font-family:Calibri,Helvetica,sans-serif,serif,EmojiFont;font-size:16px">rs10902758
NC_000004.12:g.654854G>A XM_011513473.2:c.1177G>A</div>
<div><br>
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<div>ॐ<br>
Michael Yourshaw<br>
<a href="mailto:myourshaw@ucla.edu" target="_blank"
moz-do-not-send="true">myourshaw@gmail.com</a><br>
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