Question regarding alleles

[Gabriele Zucca]

Dear HGVS Nomenclature group,

I have a question regarding the nomenclature of a variant that is described in an article by Lorenzini et al. (PMID: 32278790). In particular, the authors found a variant in NFKB1 that they describe (Table S1, variant #28) as a deletion (c.950_964del, p.(Pro317_Ile322delinsLeu)) followed by a substitution (c.967A>T, p.(Asn323Tyr)). It is not specified in the table, but I assume the two changes are in cis. According to my understanding, the variant should be described as "c.[950_964del;967A>T]" for the DNA change and "p.[(Pro317_Ile322delinsLeu);(Asn323Tyr)]" for the protein change, given that there are two "normal" TT nucleotides between the deletion and the T-to-A substitution. When I enter the "c" variant in Mutalyzer, however, it normalizes it as "c.950_967delinsTTT" and "p.(Pro317_Asn323delinsLeuTyr)". I kindly ask you which version is correct. Additionally, I think that, on the HGVS Nomenclature website, it could be useful to specify whenever, when a deletion/insertion/duplication is followed by another variant, the position for the second variant should refer the position in the original sequence or in the sequence "modified" by the first variant. Thanks in advance.

Best regards,

Gabriele Zucca, MD.

[Johan den Dunnen]

Dear Gabriele,

to answer your question, I follow the pending recommendation of SVD-WG010 (see https://hgvs-nomenclature.org/stable/consultation/SVD-WG010/). In addition I assume both variants are on 1 allele and that you used NM_003998.4 as a reference sequence. Following this recommendation, the variant should be described as NM_003998.4:c.[950_964del;967A>T] p.[(Pro317_Asn323delinsLeuTyr)]. However, SVD-WG010 gives you the freedom to use NM_003998.4:c.950_967delinsTTT ("Data providers may report adjacent variants independently and may merge nearby (non-adjacent) variants if they believe that those forms are more suitable for their data").

Please note, the description p.[(Pro317_Ile322delinsLeu);(Asn323Tyr)] does not follow HGVS nomenclature since Ile322 and Asn323 are separated by fewer than two intervening residues.

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)
http://www.HGVS.org/varnomen

Op donderdag 14 november 2024 om 23:24:28 UTC+1 schreef zuccaga...@gmail.com:

[Johan den Dunnen]

sorry, just forgot, regarding your remark whether "the position for the second variant should refer to the position in the original sequence or in the sequence 'modified' by the first variant"; for numbering residues HGVS nomenclature uses the reference sequence only.

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)
http://www.HGVS.org/varnomen

Op woensdag 20 november 2024 om 15:53:52 UTC+1 schreef Johan den Dunnen:

[Gabriele Zucca]

Thank you very much.

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