Predefined Protein Descriptions: p.? vs. p.(=) : Clarification request regarding Intronic variants

[David Hernandez]

Dear HGVS experts,

I am seeking clarification on the most appropriate predicted protein description for intronic variants, specifically regarding the use of p.? and p.(=) as defined in the HGVS recommendations from https://hgvs-nomenclature.org/stable/recommendations/uncertain/#protein :

• p.?
  used to indicate that an effect on the protein level is expected, but that it is not possible to give a reliable prediction of the consequences.
• p.(=)
  used to indicate that no changes on the protein level are expected (RNA not analysed).

Consider the example of a simple SNV occurring at a +100 intronic position:

• NC_000003.11(NM_001904.4):c.1081+100A>T

In the absence of additional information, I would argue that p.(=) is the most appropriate description, as it suggests no changes are expected at the protein level (RNA not analyzed).

However, there is no consensus on this, as the main publicly available  annotation systems differ in their predictions:

• The Mutalyzer reports p.(=), which aligns with my understanding
• The Variant Validator reports p.?, indicating an expected effect on the protein level
•  The Ensembl VEP system does not report any HGVS protein description for this variant.

As a side question: Is there a specific reason why the HGVS recommendation page mentioned above provides a definition for p.? and not fpr p.(?) ? Looking at the RNA section, both r.? and r.(?) are specifically defined.

Thanks for any clarifications on these points.

Best regards,
David Hernandez

Sophia Genetics SA

https://www.sophiagenetics.com/

[Johan den Dunnen]

Dear David,

following HGVS nomenclature, the best format to use seems NC_000003.11(NM_001904.4):c.1081+100A>T r.(?) p.(=). Using this format, you indicate that you do not expect the variant will have consequences on protein level ("p.(=)") but that you did not study RNA ("r.(?)").

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)

Op donderdag 24 oktober 2024 om 11:02:00 UTC+2 schreef david.g.h...@gmail.com:

[David Hernandez]

Dear John,
Thank you, this makes sense.
Then, p.(=) alone would work too, since it already indicates that the RNA has not been analysed.

Best,
David