<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 Brad,</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;">Did you download the database as listed in the plugin docs or did you generate it yourself?</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;">The database listed in the plugin docs was generated from release 85 of Ensembl (GRCh38), which used PolyPhen 2.2.2 (release 405, see <a href="http://jul2016.archive.ensembl.org/info/genome/variation/predicted_data.html">http://jul2016.archive.ensembl.org/info/genome/variation/predicted_data.html</a>); it has not been updated since then. We can look into generating this database each Ensembl release, for example, if there is enough demand.</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;">The date of the database’s generation is unlikely to have any effect on your analysis as the database is indexed on a digest of the reference protein sequence, so if the protein sequence VEP is analysing exists in the database you will get scores for it. When new proteins are added to the Ensembl gene set, they are inserted into the database additively, so the scores for existing sequences will not change.</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;">Hope that’s clearer</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;">Will McLaren</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;">Ensembl Variation</div> <br> <div id="bloop_sign_1498656481163207936" class="bloop_sign"></div> <br><p class="airmail_on">On 28 June 2017 at 14:13:51, Crone, Bradley (<a href="mailto:bradley-crone@uiowa.edu">bradley-crone@uiowa.edu</a>) wrote:</p> <blockquote type="cite" class="clean_bq"><span><div dir="ltr"><div></div><div>
<title></title>
<div id="divtagdefaultwrapper" style="font-size:12pt;color:#000000;font-family:Calibri,Helvetica,sans-serif;" dir="ltr">
<p>Hello,</p>
<p><br></p>
<p>I'm resending this question, since I'm not seeing an answer to
this in the dev-list.</p>
<p><font style="font-family: Calibri,Helvetica,sans-serif,serif,"EmojiFont";" face="Calibri,Helvetica,sans-serif" size="3" color="black"><span style="font-size:12pt;" id="divtagdefaultwrapper"></span></font></p>
<div style="margin-top:0;margin-bottom:0;"><font style="font-family: Calibri,Helvetica,sans-serif,serif,"EmojiFont";" face="Calibri,Helvetica,sans-serif" size="3" color="black"><span style="font-size:12pt;" id="divtagdefaultwrapper"><font face="Calibri,Helvetica,sans-serif,EmojiFont,Apple Color Emoji,Segoe UI Emoji,NotoColorEmoji,Segoe UI Symbol,Android Emoji,EmojiSymbols">
In regards to PolyPhen2 discrepancies between VEP 88 and dbNSFP
v3.0, I do have more questions about
this.</font></span></font></div>
<div style="margin-top:0;margin-bottom:0;"><font style="font-family: Calibri,Helvetica,sans-serif,serif,"EmojiFont";" face="Calibri,Helvetica,sans-serif" size="3" color="black"><span style="font-size:12pt;" id="divtagdefaultwrapper"><font face="Calibri,Helvetica,sans-serif,EmojiFont,Apple Color Emoji,Segoe UI Emoji,NotoColorEmoji,Segoe UI Symbol,Android Emoji,EmojiSymbols">
What version of PolyPhen is VEP 88 utilizing for GRCh37? I thought
I saw somewhere PolyPhen 2.2.2 was used, which should match dbNSFP
v3.0.</font></span></font></div>
<div style="margin-top:0;margin-bottom:0;"><font style="font-family: Calibri,Helvetica,sans-serif,serif,"EmojiFont";" face="Calibri,Helvetica,sans-serif" size="3" color="black"><span style="font-size:12pt;" id="divtagdefaultwrapper"><font face="Calibri,Helvetica,sans-serif,EmojiFont,Apple Color Emoji,Segoe UI Emoji,NotoColorEmoji,Segoe UI Symbol,Android Emoji,EmojiSymbols">
Additionally, I am running VEP with the PolyPhen-SIFT plugin. What
effect would this have on discrepancies?<br>
<br>
Thank you,<br>
Brad<br></font></span></font></div>
<br></div>
<hr style="display:inline-block;width:98%" tabindex="-1">
<div id="divRplyFwdMsg" dir="ltr"><font face="Calibri, sans-serif" style="font-size:11pt" color="#000000"><b>From:</b> Crone,
Bradley<br>
<b>Sent:</b> Wednesday, June 14, 2017 3:29:29 PM<br>
<b>To:</b> Ensembl developers list<br>
<b>Subject:</b> Re: [ensembl-dev] PolyPhen2 prediction
discrepancies between VEP 88 and dbNSFP v3.0</font>
<div> </div>
</div>
<div>
<div id="divtagdefaultwrapper" style="font-size:12pt;color:#000000;font-family:Calibri,Helvetica,sans-serif;" dir="ltr">
<div id="divtagdefaultwrapper" dir="ltr" style="font-size: 12pt; color: rgb(0, 0, 0); font-family: Calibri,Helvetica,sans-serif,"EmojiFont","Apple Color Emoji","Segoe UI Emoji",NotoColorEmoji,"Segoe UI Symbol","Android Emoji",EmojiSymbols;">
<p>After thinking about this more, I do have more questions about
these discrepancies.</p>
<p>What version of PolyPhen is VEP 88 utilizing for GRCh37? I
thought I saw somewhere PolyPhen 2.2.2 was used, which should match
dbNSFP v3.0.</p>
<p>Additionally, I am running VEP with the PolyPhen-SIFT plugin.
What effect would this have on discrepancies?</p>
<p><br></p>
<p>Brad<br></p>
</div>
<hr tabindex="-1" style="display:inline-block; width:98%">
<div id="divRplyFwdMsg" dir="ltr"><font style="font-size:11pt" color="#000000" face="Calibri, sans-serif"><b>From:</b> Dev
<dev-bounces@ensembl.org> on behalf of Crone, Bradley
<bradley-crone@uiowa.edu><br>
<b>Sent:</b> Tuesday, June 13, 2017 8:08:01 AM<br>
<b>To:</b> Ensembl developers list<br>
<b>Subject:</b> Re: [ensembl-dev] PolyPhen2 prediction
discrepancies between VEP 88 and dbNSFP v3.0</font>
<div> </div>
</div>
<div>
<div id="divtagdefaultwrapper" dir="ltr" style="font-size: 12pt; color: rgb(0, 0, 0); font-family: Calibri,Arial,Helvetica,sans-serif,"EmojiFont","Apple Color Emoji","Segoe UI Emoji",NotoColorEmoji,"Segoe UI Symbol","Android Emoji",EmojiSymbols;">
<p>Yes, I did inadvertently include those two examples in my list -
predictions do not match (P vs. D), but scores do match across all
three.</p>
<p><br></p>
<p>Thanks for the information, I'll look for the update to GRCh37
in July.</p>
<p><br></p>
<p>Brad<br></p>
</div>
<hr tabindex="-1" style="display:inline-block; width:98%">
<div id="divRplyFwdMsg" dir="ltr"><font style="font-size:11pt" color="#000000" face="Calibri, sans-serif"><b>From:</b> Dev
<dev-bounces@ensembl.org> on behalf of Sarah Hunt
<seh@ebi.ac.uk><br>
<b>Sent:</b> Tuesday, June 13, 2017 6:21:26 AM<br>
<b>To:</b> Ensembl developers list<br>
<b>Subject:</b> Re: [ensembl-dev] PolyPhen2 prediction
discrepancies between VEP 88 and dbNSFP v3.0</font>
<div> </div>
</div>
<div>
<p><br></p>
<p>Hi Brad,</p>
<p><br></p>
<p>We do find differences between different PolyPhen analyses,
dependent on code version and protein databases used. Our GRCh37
database will be updated to the latest PolyPhen version in July, so
do expect some changes. There are a number of genes returning
unknown classifications in our GRCh37 databases, which have calls
in our GRCh38 databases which have already been updated to the
newer version, so we hope the update improves GRCh37 coverage. An
example from your list:<br></p>
<p><br></p>
<p><a class="moz-txt-link-freetext" href="http://grch37.ensembl.org/Homo_sapiens/Variation/Mappings?db=core;r=1:103427257-103428257;v=rs754273408;vdb=variation;vf=119985449" id="LPlnk811766" previewremoved="true">http://grch37.ensembl.org/Homo_sapiens/Variation/Mappings?db=core;r=1:103427257-103428257;v=rs754273408;vdb=variation;vf=119985449</a><br>
</p>
<p><a class="moz-txt-link-freetext" href="http://www.ensembl.org/Homo_sapiens/Variation/Mappings?db=core;r=1:102961701-102962701;v=rs754273408;vdb=variation;vf=119958041" id="LPlnk489034" previewremoved="true">http://www.ensembl.org/Homo_sapiens/Variation/Mappings?db=core;r=1:102961701-102962701;v=rs754273408;vdb=variation;vf=119958041</a></p>
<p><br></p>
<p>Thanks for the examples, but I find them a little confusing.
Don't 2 of them (10-73377145 & 1-103462662) show
agreement across all three versions?<br></p>
<p><br></p>
<p>Best wishes,</p>
<p><br></p>
<p>Sarah<br></p>
<p><br></p>
<div class="moz-cite-prefix">On 12/06/2017 17:05, Crone, Bradley
wrote:<br></div>
<blockquote type="cite">
<div id="divtagdefaultwrapper" dir="ltr" style="font-size: 12pt; color: rgb(0, 0, 0); font-family: Calibri,Arial,Helvetica,sans-serif,"EmojiFont","Apple Color Emoji","Segoe UI Emoji",NotoColorEmoji,"Segoe UI Symbol","Android Emoji",EmojiSymbols;">
<p>Hello,</p>
<p><br></p>
<p>I'm working with PolyPhen2 scores and predictions in VEP 88 and
comparing these back to scores reported in dbNSFP v3.0.</p>
<p>I find a large number of discrepancies between HumDiv scores
from VEP and dbNSFP. I've looked at a small subset of 10
mismatches.</p>
<p>Directly comparing scores/predictions with PolyPhen2's website,
all PolyPhen2 scores match with a dbNSFP score, and not a VEP
score:</p>
<p><br></p>
<div>CHROM POS REF
ALT GENE
VEP-FEATURE VEP-IMPACT
VEP_CSQ VEP_POLYPHEN_SCORE
VEP_POLYPHEN_PRED
DBNSFP_POLYPHEN2_HDIV_SCORE
DBNSFP_POLYPHEN2_HDIV_PRED
pph2_prob pph2_FPR
pph2_TPR<br>
2 73679572 C
A ALMS1
NM_015120.4 MODERATE
missense_variant 0.952
P 0.987,0.972,0.026
D,D,B 0.026
0.188
0.949<br>
1 216011417 A
T USH2A
NM_206933.2 MODERATE
missense_variant 0.155
B 0.933 P
0.933 0.0573
0.804<br>
12 48398104 T
C COL2A1
NM_001844.4 HIGH
start_lost 0
U 0.219,0.14
B 0.14
0.136
0.923<br>
1 103427757 C
G COL11A1
NM_080629.2 MODERATE
missense_variant 0
U 0.999 D
0.999 0.00574
0.136<br>
12 48377197 G
T COL2A1
NM_001844.4 MODERATE
missense_variant 0.784
P 0.001,0.0 B
0
1
1<br>
6 70981396 C
A COL9A1
NM_001851.4 MODERATE
missense_variant 0.555
P 0.31,0.0 B
0.31
0.112 0.904<br>
10 73377145 G
A CDH23
NM_001171930.1 MODERATE
missense_variant 1
P 1.0,1.0,0.998
D 1
0.00026 0.00018<br>
1 216496954 T
C USH2A
NM_206933.2 MODERATE
missense_variant 1
P 0.971,0.413
D,B 0.413
0.103
0.893<br>
17 18064707 C
A MYO15A
NM_016239.3 MODERATE
missense_variant 0
U
0.941,0.761,0.165,0.523,0.981,0.953
P,P,B,P,D,P 0.523
0.0959
0.882<br>
1 103462662 C
T COL11A1
NM_001190709.1 MODERATE
missense_variant 1
P 1.0 D
1 0.00026
0.00018</div>
<br>
<p>Any idea for this discrepancy?</p>
<p><br></p>
<p>Thanks,</p>
<p>Brad<br></p>
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