CLINVAR multiple molecular consequences

Question

[cocchi.e89]

Dear all,

I've noticed that in CLINVAR multiple "molecular consequences" are showed for each variant, as example: https://www.ncbi.nlm.nih.gov/clinvar/variation/221294/ is indicated as: NM_020771.3(HACE1):c.454C>T (p.Gln152Ter) but in the section molecular consequence 4 different variants are showed:

• NM_001321080.1:c.402+10101C>T: intron variant SO:0001627
• NM_001321084.1:c.33C>T: synonymous variant SO:0001819
• NM_020771.3:c.454C>T: nonsense SO:0001587
• NR_104424.1:n.731C>T: non-coding transcript variant SO:0001619

Does somebody knows why?

Thanks a lot in advance for any help!

[vkkodali_ncbi]

Each one of those NM and NR accessions appear to be alternate splice variants encoded by the gene HACE1. Depending on the coding sequence, and where it ends up in that particular alt splice variant, the consequence can be different. In the case of NM_020771.3, a C>T mutation would result in a termination codon whereas in NM_001321084.1, the same mutation would end up being synonymous. You may want to look at this genomic position (NC_000006.12: 104833122) in Genome Data Viewer to get a better idea of how this mutation would affect each of the splice variants of the gene.

[cpad0112]

Consequence calculations are, in general, transcript specific for any given gene. Probably that is the reason VEP has an option to report most deleterious effect for any given variation in coding region. cocchi.e89

[cocchi.e89]

Sorry cpad, I don’t get you, do you mean that this specific mutation results in 4 different consequences depending on the gene splice variant transcript? Or are you pointing out something else?

[cpad0112]

the four molecular consequences you are seeing, are for chromosomal variation (Chr6:g.104833122C>T). This chromosomal variation can be back calculated from NM_020771.3(HACE1):c.454C>T (p.Gln152Ter).

At position Chr6:104833122 (GRCh38 build), there are four transcripts possible and the variation at genomic location, may result in 4 different consequences for each transcript. Of 4 calculated consequences, one of the calculated consequence is NM_020771.3(HACE1):c.454C>T (p.Gln152Ter), and this is a nonsense variation (Gln to stop) in transcript NM_020771.3.

cocchi.e89