<div dir="ltr"><div dir="ltr"><div dir="ltr">Hi Sarah,</div><div dir="ltr"><br></div><div>I am not trying to put any pressure but just wonder if you guys are checking the cause of inconsistency.</div><div><br></div><div>And one more observation is that the REST API is also returning score that is same as that from VEP cache result for the aforementioned variant:</div><div><br></div><div><font face="monospace, monospace">curl -sH 'Accept: application/json' '<a href="http://grch37.rest.ensembl.org/vep/human/hgvs/NM_152486.2:c.83G%3EA?refseq=1&hgvs=1">http://grch37.rest.ensembl.org/vep/human/hgvs/NM_152486.2:c.83G%3EA?refseq=1&hgvs=1</a>' | python -m json.tool | grep polyphen_score</font><br></div><div dir="ltr"><br></div><div>I would guess that VEP cache is being used by the REST server for result lookup.</div><div dir="ltr"><br clear="all"><div><div dir="ltr" class="gmail_signature"><div dir="ltr">Thanks,<div>Wallace</div></div></div></div><br></div><br><div class="gmail_quote"><div dir="ltr">On Tue, Jan 15, 2019 at 8:13 PM Wallace Ko <<a href="mailto:myko@l3-bioinfo.com">myko@l3-bioinfo.com</a>> wrote:<br></div><blockquote class="gmail_quote" style="margin:0px 0px 0px 0.8ex;border-left:1px solid rgb(204,204,204);padding-left:1ex"><div dir="ltr"><div dir="ltr"><div dir="ltr">Hi Sarah,<div><br></div><div>I have further tested different versions of VEP (GRCh37, RefSeq) and found something interesting for the variant NM_152486.2:c.83G>A (chr1_865545_G/A).<br><div>The table below list PolyPhen2 scores for the variant from 3 versions of VEP, one from cache and the other from Ensembl database:<br></div><div><br></div><div><table cellspacing="0" cellpadding="0" dir="ltr" border="1" style="table-layout:fixed;font-size:10pt;font-family:arial,sans,sans-serif;width:0px;border-collapse:collapse;border:none"><colgroup><col width="60"><col width="53"><col width="77"></colgroup><tbody><tr style="height:21px"><td style="border:1px solid rgb(0,0,0);overflow:hidden;padding:2px 3px;vertical-align:bottom">Version</td><td style="border-width:1px;border-style:solid;border-color:rgb(0,0,0) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom">Cache</td><td style="border-width:1px;border-style:solid;border-color:rgb(0,0,0) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom">Database</td></tr><tr style="height:21px"><td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0);overflow:hidden;padding:2px 3px;vertical-align:bottom;text-align:right">92</td><td style="text-align:right;border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom">-</td><td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom;text-align:right">0.778</td></tr><tr style="height:21px"><td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0);overflow:hidden;padding:2px 3px;vertical-align:bottom;text-align:right">94</td><td style="text-align:right;border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom">-</td><td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom;text-align:right">0.778</td></tr><tr style="height:21px"><td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0);overflow:hidden;padding:2px 3px;vertical-align:bottom;text-align:right">95</td><td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom;text-align:right">0.913</td><td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom;text-align:right">0.778</td></tr></tbody></table></div><div><br></div><div>First, why the scores from cache and database are different?</div><div><br></div><div>Assuming the scores from cache are correct, the score is changed from none in v94 to 0.913 in v95. However, according to the <a href="https://www.ensembl.org/info/docs/tools/vep/script/vep_download.html#history" target="_blank">release history,</a> RefSeq transcript was updated in v94. Does this update affect GRCh37 cache? If so, why score is changed in v95 instead of v94? Otherwise, what causes the change (e.g. you have rerun the PolyPhen pipeline again) ?</div><div>If the change in score from cache is expected, it would be great to have a way (e.g. a release log message) for us to know that there is chance for the scores to change in a new release.</div><div><br></div><div>Thanks</div><div><br clear="all"><div><div dir="ltr" class="gmail-m_-8920091978338228719m_4799972173951499759m_-750635253524879009m_-2967733834665796768gmail_signature"><div dir="ltr">Regards,<div>Wallace</div></div></div></div><br></div></div></div></div></div><br><div class="gmail_quote"><div dir="ltr">On Fri, Jan 4, 2019 at 7:37 PM Sarah Hunt <<a href="mailto:seh@ebi.ac.uk" target="_blank">seh@ebi.ac.uk</a>> wrote:<br></div><blockquote class="gmail_quote" style="margin:0px 0px 0px 0.8ex;border-left:1px solid rgb(204,204,204);padding-left:1ex">
<div bgcolor="#FFFFFF">
<p><br>
</p>
<p>Hi Wallace,</p>
<p>Both NCBI and Ensembl stopped creating new gene annotations on
GRCh37 a long time ago - late 2013 and early 2014 respectively.<br>
</p>
<p>NCBI released a mapping of the then current set of GRCh38-derived
RefSeq transcripts to GRCh37 in January 2017. (See:
<a class="gmail-m_-8920091978338228719gmail-m_4799972173951499759gmail-m_-750635253524879009gmail-m_-2967733834665796768gmail-m_2016991112381052549moz-txt-link-freetext" href="ftp://ftp.ncbi.nlm.nih.gov/genomes/H_sapiens/GRCh37.p13_interim_annotation/README" target="_blank">ftp://ftp.ncbi.nlm.nih.gov/genomes/H_sapiens/GRCh37.p13_interim_annotation/README</a>
for details). We added these to our GRCh37 database in Ensembl
90, in the summer of 2017, with SIFT and PolyPhen2 results. <br>
</p>
<p>We are not expecting any new transcript data for GRCh37, so there
is nothing new to analyse. If we switch to new versions of SIFT or
Polyphen2 or find ways to reduce the failure rate, we may update
the GRCh37 results. We don't currently plan a version change and
it would be announced if we did this as results would change.</p>
<p>Best wishes,</p>
<p>Sarah<br>
</p>
<div class="gmail-m_-8920091978338228719gmail-m_4799972173951499759gmail-m_-750635253524879009gmail-m_-2967733834665796768gmail-m_2016991112381052549moz-cite-prefix">On 04/01/2019 02:16, Wallace Ko wrote:<br>
</div>
<blockquote type="cite">
<div dir="ltr">Hi Sarah,
<div><br>
</div>
<div>Thanks for your explanation.</div>
<div>Does it mean that SIFT and PolyPhen2 scores for RefSeq
transcript for GRCh37 are now also calculated (instead of
mapping from Ensembl transcript) but at a longer update
interval?</div>
<div><br clear="all">
<div>
<div dir="ltr" class="gmail-m_-8920091978338228719gmail-m_4799972173951499759gmail-m_-750635253524879009gmail-m_-2967733834665796768gmail-m_2016991112381052549gmail_signature">
<div dir="ltr">Best,
<div>Wallace</div>
</div>
</div>
</div>
<br>
</div>
</div>
<br>
<div class="gmail_quote">
<div dir="ltr">On Thu, Jan 3, 2019 at 1:09 AM Sarah Hunt <<a href="mailto:seh@ebi.ac.uk" target="_blank">seh@ebi.ac.uk</a>>
wrote:<br>
</div>
<blockquote class="gmail_quote" style="margin:0px 0px 0px 0.8ex;border-left:1px solid rgb(204,204,204);padding-left:1ex">
<div bgcolor="#FFFFFF">
<p><br>
</p>
<p>Hi Wallace,</p>
<p>Apologies for the partial response. <br>
</p>
<p>Prior to release 90, we did not calculate SIFT and
PolyPhen2 scores for RefSeq transcripts, though they were
available for those with translations identical to an
Ensembl transcript. Although the GRCh37 transcript sets
have been frozen for some time, we update our GRCh37
variation data roughly annually, and results from the
analysis of new Ensembl GRCh38 translations would be made
available then. <br>
</p>
<p>The difference in SIFT results - the change from no data
to a prediction - will be due to results for a transcript
matching NM_000540.2 becoming available in release 88.</p>
<p>We re-ran our PolyPhen pipeline for e!90 when we noticed
slightly lower missingness rates after a change of
hardware. We suspected changes in the cluster set up led
to less high-memory alignment failures, but were not in a
position to test this.</p>
<p>We now routinely calculate SIFT and PolyPhen2 scores for
RefSeq transcripts for our GRCh38 releases, which happen
roughly quarterly. Due to the scheduling of when RefSeq
transcript data becomes available in our release process,
these scores are available in VEP the release after the
transcripts are available.<br>
</p>
<p>Best wishes,</p>
<p>Sarah<br>
</p>
<br>
<blockquote type="cite">
<div class="gmail-m_-8920091978338228719gmail-m_4799972173951499759gmail-m_-750635253524879009gmail-m_-2967733834665796768gmail-m_2016991112381052549gmail-m_3254829721660434728moz-cite-prefix">On
28/12/2018 11:12, Wallace Ko wrote:<br>
</div>
<blockquote type="cite">
<div dir="ltr">
<div dir="ltr">
<div dir="ltr">
<div dir="ltr">
<div dir="ltr">
<div dir="ltr">
<div dir="ltr">
<div dir="ltr">Hello,
<div><br>
</div>
<div>For the
variant chr19:g.39075695C>T, the
SIFT and PolyPhen score are changed in
recent versions of VEP.</div>
<div><br>
</div>
<div>
<table dir="ltr" style="table-layout:fixed;font-size:10pt;font-family:arial,sans,sans-serif;width:0px;border-collapse:collapse;border:none" cellspacing="0" cellpadding="0" border="1">
<colgroup><col width="42"><col width="171"><col width="100"><col width="167"></colgroup><tbody>
<tr style="height:21px">
<td style="border:1px solid rgb(0,0,0);overflow:hidden;padding:2px 3px;vertical-align:bottom">VEP</td>
<td style="border-width:1px;border-style:solid;border-color:rgb(0,0,0) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom">HGVSc</td>
<td style="border-width:1px;border-style:solid;border-color:rgb(0,0,0) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom">SIFT</td>
<td style="border-width:1px;border-style:solid;border-color:rgb(0,0,0) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom">PolyPhen</td>
</tr>
<tr style="height:21px">
<td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0);overflow:hidden;padding:2px 3px;vertical-align:bottom;text-align:right">87</td>
<td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom">NM_000540.2:c.14759C>T</td>
<td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom">-</td>
<td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom">unknown(0)</td>
</tr>
<tr style="height:21px">
<td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0);overflow:hidden;padding:2px 3px;vertical-align:bottom;text-align:right">88</td>
<td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom">NM_000540.2:c.14759C>T</td>
<td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom">deleterious(0)</td>
<td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom">unknown(0)</td>
</tr>
<tr style="height:21px">
<td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0);overflow:hidden;padding:2px 3px;vertical-align:bottom;text-align:right">89</td>
<td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom">NM_000540.2:c.14759C>T</td>
<td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom">deleterious(0)</td>
<td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom">unknown(0)</td>
</tr>
<tr style="height:21px">
<td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0);overflow:hidden;padding:2px 3px;vertical-align:bottom;text-align:right">90</td>
<td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom">NM_000540.2:c.14759C>T</td>
<td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom">deleterious(0)</td>
<td style="border-width:1px;border-style:solid;border-color:rgb(204,204,204) rgb(0,0,0) rgb(0,0,0) rgb(204,204,204);overflow:hidden;padding:2px 3px;vertical-align:bottom">probably_damaging(0.998)</td>
</tr>
</tbody>
</table>
</div>
<div><br>
</div>
<div>The above table shows that
for NM_000540.2:c.14759C>T, SIFT is
changed from '-' to 'deleterious(0)'
since VEP 88 and PolyPhen is changed
from 'unknown(0)' to
'probably_damaging(0.998)' since VEP
90.</div>
<div><br>
</div>
<div>There is no change in software
version of SIFT (sift5.2.2) and
PolyPhen (2.2.2) in these versions of
VEP, so I wonder what causes to the
change in the prediction scores.</div>
<div><br>
</div>
<div>Thank you.</div>
<div><br clear="all">
<div>
<div dir="ltr" class="gmail-m_-8920091978338228719gmail-m_4799972173951499759gmail-m_-750635253524879009gmail-m_-2967733834665796768gmail-m_2016991112381052549gmail-m_3254829721660434728gmail_signature">
<div dir="ltr">Regards,
<div>Wallace Ko</div>
</div>
</div>
</div>
</div>
</div>
</div>
</div>
</div>
</div>
</div>
</div>
</div>
<br>
<fieldset class="gmail-m_-8920091978338228719gmail-m_4799972173951499759gmail-m_-750635253524879009gmail-m_-2967733834665796768gmail-m_2016991112381052549gmail-m_3254829721660434728mimeAttachmentHeader"></fieldset>
<pre class="gmail-m_-8920091978338228719gmail-m_4799972173951499759gmail-m_-750635253524879009gmail-m_-2967733834665796768gmail-m_2016991112381052549gmail-m_3254829721660434728moz-quote-pre">_______________________________________________
Dev mailing list <a class="gmail-m_-8920091978338228719gmail-m_4799972173951499759gmail-m_-750635253524879009gmail-m_-2967733834665796768gmail-m_2016991112381052549gmail-m_3254829721660434728moz-txt-link-abbreviated" href="mailto:Dev@ensembl.org" target="_blank">Dev@ensembl.org</a>
Posting guidelines and subscribe/unsubscribe info: <a class="gmail-m_-8920091978338228719gmail-m_4799972173951499759gmail-m_-750635253524879009gmail-m_-2967733834665796768gmail-m_2016991112381052549gmail-m_3254829721660434728moz-txt-link-freetext" href="http://lists.ensembl.org/mailman/listinfo/dev" target="_blank">http://lists.ensembl.org/mailman/listinfo/dev</a>
Ensembl Blog: <a class="gmail-m_-8920091978338228719gmail-m_4799972173951499759gmail-m_-750635253524879009gmail-m_-2967733834665796768gmail-m_2016991112381052549gmail-m_3254829721660434728moz-txt-link-freetext" href="http://www.ensembl.info/" target="_blank">http://www.ensembl.info/</a>
</pre>
</blockquote>
<br>
<fieldset class="gmail-m_-8920091978338228719gmail-m_4799972173951499759gmail-m_-750635253524879009gmail-m_-2967733834665796768gmail-m_2016991112381052549gmail-m_3254829721660434728mimeAttachmentHeader"></fieldset>
<pre class="gmail-m_-8920091978338228719gmail-m_4799972173951499759gmail-m_-750635253524879009gmail-m_-2967733834665796768gmail-m_2016991112381052549gmail-m_3254829721660434728moz-quote-pre">_______________________________________________
Dev mailing list <a class="gmail-m_-8920091978338228719gmail-m_4799972173951499759gmail-m_-750635253524879009gmail-m_-2967733834665796768gmail-m_2016991112381052549gmail-m_3254829721660434728moz-txt-link-abbreviated" href="mailto:Dev@ensembl.org" target="_blank">Dev@ensembl.org</a>
Posting guidelines and subscribe/unsubscribe info: <a class="gmail-m_-8920091978338228719gmail-m_4799972173951499759gmail-m_-750635253524879009gmail-m_-2967733834665796768gmail-m_2016991112381052549gmail-m_3254829721660434728moz-txt-link-freetext" href="http://lists.ensembl.org/mailman/listinfo/dev" target="_blank">http://lists.ensembl.org/mailman/listinfo/dev</a>
Ensembl Blog: <a class="gmail-m_-8920091978338228719gmail-m_4799972173951499759gmail-m_-750635253524879009gmail-m_-2967733834665796768gmail-m_2016991112381052549gmail-m_3254829721660434728moz-txt-link-freetext" href="http://www.ensembl.info/" target="_blank">http://www.ensembl.info/</a>
</pre>
</blockquote>
</div>
_______________________________________________<br>
Dev mailing list <a href="mailto:Dev@ensembl.org" target="_blank">Dev@ensembl.org</a><br>
Posting guidelines and subscribe/unsubscribe info: <a href="http://lists.ensembl.org/mailman/listinfo/dev" rel="noreferrer" target="_blank">http://lists.ensembl.org/mailman/listinfo/dev</a><br>
Ensembl Blog: <a href="http://www.ensembl.info/" rel="noreferrer" target="_blank">http://www.ensembl.info/</a><br>
</blockquote>
</div>
<br>
<fieldset class="gmail-m_-8920091978338228719gmail-m_4799972173951499759gmail-m_-750635253524879009gmail-m_-2967733834665796768gmail-m_2016991112381052549mimeAttachmentHeader"></fieldset>
<pre class="gmail-m_-8920091978338228719gmail-m_4799972173951499759gmail-m_-750635253524879009gmail-m_-2967733834665796768gmail-m_2016991112381052549moz-quote-pre">_______________________________________________
Dev mailing list <a class="gmail-m_-8920091978338228719gmail-m_4799972173951499759gmail-m_-750635253524879009gmail-m_-2967733834665796768gmail-m_2016991112381052549moz-txt-link-abbreviated" href="mailto:Dev@ensembl.org" target="_blank">Dev@ensembl.org</a>
Posting guidelines and subscribe/unsubscribe info: <a class="gmail-m_-8920091978338228719gmail-m_4799972173951499759gmail-m_-750635253524879009gmail-m_-2967733834665796768gmail-m_2016991112381052549moz-txt-link-freetext" href="http://lists.ensembl.org/mailman/listinfo/dev" target="_blank">http://lists.ensembl.org/mailman/listinfo/dev</a>
Ensembl Blog: <a class="gmail-m_-8920091978338228719gmail-m_4799972173951499759gmail-m_-750635253524879009gmail-m_-2967733834665796768gmail-m_2016991112381052549moz-txt-link-freetext" href="http://www.ensembl.info/" target="_blank">http://www.ensembl.info/</a>
</pre>
</blockquote>
</div>
_______________________________________________<br>
Dev mailing list <a href="mailto:Dev@ensembl.org" target="_blank">Dev@ensembl.org</a><br>
Posting guidelines and subscribe/unsubscribe info: <a href="http://lists.ensembl.org/mailman/listinfo/dev" rel="noreferrer" target="_blank">http://lists.ensembl.org/mailman/listinfo/dev</a><br>
Ensembl Blog: <a href="http://www.ensembl.info/" rel="noreferrer" target="_blank">http://www.ensembl.info/</a><br>
</blockquote></div>
</blockquote></div></div></div>