Delins in intronic region
Irina RB
Dear HGVS team,
We were asked to study 2 variants in intron 6 of EFTUD2 gene: 17:42960453delCTA and 17:42960458T>G. Should we define it as a delins variant o as 2 separated variants?
This is how we see them using IGV program:
When we perform a search in Alamut of both variants as a delins, g. positions get transformed because Alamut is supposed to use the 3’ rule:
Separately, each one would be:
And
Positions in the deletion have been converted to those HGVS compliant, so now both variants are adjacent. Also, we noticed that cDNA nomenclature still follows the HGVS non-compliant positions (c.492+6_492+8del instead of c.2492+4_492+6del corresponding to 42960455_42960457del HGVS compliant position).
We feel really confused about how does the 3’ rule work for reverse genes, and specially in intronic regions. We’d like to know more about this rule and confirm how we should inform this finding, as a single delins variant or 2 separated variants.
We’re looking forward to hearing from you.
Kind regards.
Johan den Dunnen
NM_004247.4 for the EFTUD2 coding DNA reference sequence. Regarding the 3'rule, it is always applied relative to the reference sequence used.
Following HGVS nomenclature, applying the 3' rule, the variant can be best described as NC_000017.10:g.42960455_42960458delinsG NM_004247.4:c.492+3_492+6delinsC. Indeed, in theory, since the EFTUD2 gene is on the - strand, you could also describe the variant as c.[492+3A>C;492+6_492+8del]. However, tools like Mutalyzer (www.Mutalyzer.nl) and VariantValidator (www.variantvalidator.org) both suggest to use NM_004247.4:c.492+3_492+6delinsC instead.
Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)