Question regarding HGVS classification of a deletion introducing an immediate stop codon

[Deivid Souza]

Dear HGVS Nomenclature Committee,

Hello, I would like to ask for clarification regarding the description and classification of a specific variant according to the HGVS recommendations.

The variant is:

Gene: CDH1
Reference transcript: NM_004360.5
HGVS c.: c.1350_1362del
Genomic coordinate (GRCh38): chr16-68815540-AGTACATTCTACAC-A 

Predicted protein consequence: p.Tyr450*

This variant corresponds to a deletion of 13 nucleotides that shifts the reading frame and results in the immediate creation of a stop codon at the first altered codon.

In the HGVS recommendations for frameshift variants, the following note is stated:

“NOTE: the shortest frameshift variant possible contains fsTer2; variants which introduce an immediate translation termination (stop) codon are described as nonsense variant, e.g., p.Tyr4Ter (or p.Tyr4*) not p.Tyr4TerfsTer1.”

Based on this guidance, the correct protein description appears to be p.Tyr450* (i.e., a nonsense variant), which I agree with.

However, from a mechanistic perspective, this change is caused by a frameshift due to the 13-bp deletion that leads to an immediate stop codon. Therefore, I would like to clarify how HGVS recommends classifying this type of variant.

Should this variant be considered a frameshift deletion at the DNA level that leads to an immediate stop codon, or should it be CLASSIFIED (not described) purely as a nonsense variant according to HGVS terminology?

Thank you very much for your time and for maintaining these important nomenclature guidelines.

Kind regards,

Deivid Calebe de Souza

[Johan den Dunnen]

Dear Deivid,

HGVS nomenclature is about describing variants. HGVS nomenclature is not about how to categorize a variant. HGVS nomenclature does however recommend that when you want to categorize variants, you do this separately at DNA, RNA and protein level. In the example you give the variant at DNA level seems a deletion and at RNA level is a (predicted) deletion. At protein level, following HGVS nomenclature, the variant is described as a nonsense variant, it gives an immediate translational stop. It seems arbitrary to me whether this should be called a "frame shift", I see no shifted frame, only an immediate stop (my personal opinion).

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)

Op dinsdag 17 maart 2026 om 16:51:49 UTC+1 schreef Deivid Souza: