Annovar - SIFT prediction: Multiple transcripts, which transcript is used for scoring?

Question

[vw]

Because of splicing, one variant may affect different transcripts and the effect can be different from one transcript to another. In the case where there are multiple transcripts associated to one gene, Annovar will output the information of all the transcripts.

However for the SIFT prediction (or any other SNP annotation tool - Polyphen2, Mutation Taster..), even if there are different transcripts involved by the variant, there's only one score/prediction.

For example:

C6orf25:NM_138273:exon3:c.C432G:p.F144L,C6orf25:NM_025260:exon4:c.C523G:p.R175G,C6orf25:NM_138272:exon4:c.C523G:p.R175G,C6orf25:NM_138277:exon4:c.C523G:p.R175G

Here there are 4 different transcripts listed, however the only SIFT prediction is 0.34/T.

So my question is the following: how do I know which transcript was taken into consideration for the prediction? If there's only one prediction, does that mean that it applies to all the transcript?

I am trying to understand how I can interpret the SIFT prediction in that case and any help in that regard is welcome.

Answer 1

[dandan]

On the Annovar website, it's stated that

... it can have multiple scores such as "1.0;1.0;1.0;1.0;0.993;1.0;1.0;1.0;0.999" and multiple predictions such as "D;D;D;D;D;D;D;D;D", probably due to multiple transcriptional isoforms. In this case, only the largest score (1 is the largest score among multiple isoforms), as well as its associated D/P/B annotation, will be used in ANNOVAR database."

http://www.openbioinformatics.org/annovar/annovar_filter.html#ljb23

I believe the score that ANNOVAR reports is the most deleterious score out of all the transcripts. If you want scores that are transcript specific, or to figure out which transcript that score belongs to, I suggest either going back to dbNSFP, or trying out VEP or SnpEff.

Hope that helps

[vw]

I don't know how I passed by this information on the website. Thanks for pointing that out! It's the answer I've been looking for.