consequence estimated mistake

[fzhbioinfo]

I used VEP GRCh37 web tool that '11 118898437 . C A . . .' as input.
Job result is https://grch37.ensembl.org/Homo_sapiens/Tools/VEP/Results?tl=vuAGsrPoktPMc2PM-11132921.
Why consequence gives splice_acceptor_variant ? It's actually missense_variant. It seems like it is due to the difference between RefSeq transcript and reference genome at location 11:118898436.
We look forward to your solution to this kind of consequence estimated issuse.

[likhitha-surapaneni]

Hi @fzhbioinfo , splice_acceptor_variant is assigned to variants that change 2 base region at the 3' end of an intron.

As per the annotation source for RefSeq , this variant falls within the above specified condition for the region and hence gets the splice_acceptor_variant consequence assigned.

Please let us know if this answers your question.

Kind regards,
Likhitha

[fzhbioinfo]

Hi @likhitha-surapaneni
Thank you for your reply! I can understand the reason that the consequence output is splice_acceptor_variant. It is due to the difference between RefSeq transcript and reference genome at location 11:118898436, but in fact this variation is not in the intron area. Therefore, more severe consequence gives splice_acceptor_variant which is inaccurate.

[likhitha-surapaneni]

Hi @fzhbioinfo, thank you for explaining this clearly. We are investigating this further.

[likhitha-surapaneni]

Hi @fzhbioinfo ,

After investigating it further and discussing with the team, this seems to be the case where there is not a good mapping between the transcript and the reference genome assembly which results in a false 1 base intron and this confounds the consequence calling. You can see the problem in the gene annotation file -

NC_000011.9	BestRefSeq	exon	118898437	118898582	.	-	.	ID=exon-NM_001164279.2-5;Parent=rna-NM_001164279.2;Dbxref=GeneID:2542,Genbank:NM_001164279.2,HGNC:HGNC:4061,MIM:602671;Note=The RefSeq transcript has 1 frameshift compared to this genomic sequence;exception=annotated by transcript or proteomic data;gbkey=mRNA;gene=SLC37A4;inference=similar to RNA sequence%2C mRNA (same species):RefSeq:NM_001164279.2;product=solute carrier family 37 member 4%2C transcript variant 3;transcript_id=NM_001164279.2
NC_000011.9	BestRefSeq	exon	118898338	118898435	.	-	.	ID=exon-NM_001164279.2-6;Parent=rna-NM_001164279.2;Dbxref=GeneID:2542,Genbank:NM_001164279.2,HGNC:HGNC:4061,MIM:602671;Note=The RefSeq transcript has 1 frameshift compared to this genomic sequence;exception=annotated by transcript or proteomic data;gbkey=mRNA;gene=SLC37A4;inference=similar to RNA sequence%2C mRNA (same species):RefSeq:NM_001164279.2;product=solute carrier family 37 member 4%2C transcript variant 3;transcript_id=NM_001164279.2

This kind of issue impacts a number of transcripts on GRCh37. Many such regions have been fixed in GRCh38, but this region is only correctly represented in the fix patch, which we are aware a lot of people don’t use.

Hope this answers your question.

Kind regards,
Likhitha

[fzhbioinfo]

Hi @likhitha-surapaneni ,
Thank you very much for your answer! I checked GCF_000001405.25_GRCh37.p13_knownrefseq_alns.bam and GCF_000001405.40_GRCh38.p14_knownrefseq_alns.bam and found that a large number of transcripts have this problem.
Please let me know if you have any plans and ideas to optimize the more serve consequence estimation problem in this case.

[likhitha-surapaneni]

HI @fzhbioinfo ,

Thank you for getting back. Currently this is not in our immediate plans due to limited priorities.
Hope this answers your question.

Kind regards,
Likhitha