HGVS RNA nomenclature for pseudoexon inclusion events

[Obdulia Sánchez Lijarcio]

Dear colleagues,

I have a question regarding HGVS RNA nomenclature for pseudoexon inclusion events.

To illustrate my question, I will use the variant NC_000012.12:g.102854533A>C NM_000277.3:c.706+603T>G reported in the paper DOI:10.1016/j.jmoldx.2023.02.001

This deep intronic variant results in the inclusion of a pseudoexon derived from intronic sequence approximately corresponding to c.706+534 to c.706+647. The inserted pseudoexon contains the causative variant itself, meaning that the sequence present in the RNA differs from the reference intronic sequence at position c.706+603.

After reading the HGVS recommendations and examples, I am still unsure how this situation should be described at the RNA level. My understanding is that the consequence could be written as:

r.706_707ins[706+534_c.706+647;706+603T>G]

because the inserted sequence contains the nucleotide substitution and is therefore not identical to the reference intronic sequence.

However, I am not sure whether sequence differences present within the inserted fragment should be incorporated directly into the RNA description or handled in another way.

Could someone clarify what the HGVS-compliant RNA description would be in this situation?

Thank you very much for your help.

[Johan den Dunnen]

Dear Obdulia,

following HGVS nomenclature, the correct description of the variant is NC_000012.12:g.102854533A>C NM_000277.3:c.706+603T>G r.706_707ins[c.706+534_706+602;c.706+603T>G;c.706+604_706+647].

Indeed not all details for this description are on the nomenclature website yet. However, there is currently Community Consultation Proposal SVD-WG011 (RNA insertions), which is open for comments (see https://hgvs-nomenclature.org/stable/consultation/SVD-WG011/). Assuming the proposal will be accepted, I applied it to answer your question.

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)

Op dinsdag 9 juni 2026 om 14:23:25 UTC+2 schreef Obdulia Sánchez Lijarcio:

[Johan den Dunnen]

Dear Obdulia,

unfortunately I made a mistake in my reply. Correct is 

NC_000012.12:g.102854533A>C NM_000277.3:c.706+603T>G r.706_707ins[c.706+534_706+602;G;c.706+604_706+647]. So ";G;" and not ";c.706+603T>G;" in the middle. Much simpler also.

Another remark. In the LOVD databases (https://databases.lovd.nl/shared/) you can often find descriptions for variants affecting splicing. I noticed the variant we discuss here is listed in the PAH gene variant database.

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)

Op dinsdag 9 juni 2026 om 15:29:33 UTC+2 schreef Johan den Dunnen:

[Obdulia Sánchez Lijarcio]

Dear Johan,

Thank you very much for taking the time to explain the correct notation and for pointing me to the LOVD database. I had not noticed that the RNA nomenclature was already specified in there. 

Best regards,

Obdulia