Variant nomenclature verification-Large deletion-insertion

[Chai Teng Chear]

Dear mutalyzer team,

Good day.

I am writing to verify the nomenclature of a variant with large deletion-insertion.

Let me briefly explain my case. There is a deletion of ~2.4kb nucleotides involving intron 7-intron10 of human BTK (NG_009616.1:g.g.30012_32416), while a sequence of ~3.6kb nucleotides have been replaced.  When performing NCBI blast, the sequence was found matched to another gene (NG_052969.1:g.788322_791554) with 92% query covered and 99.85% identity.

Therefore, I assigned a nomenclature for this variant, as below:

NG_009616.1:g.30012_32416delins[(302);NG_052969.1:g.788322_791554;GT] where the first 302 nucleotides were not matched to any sequence in the any database, followed by 99.85% matched NG_052969.1 sequence, and lastly two nucleotide, ie. GT.

However, when I submitted this nomenclature in Name Checker, it returned an error message " Only the insertion of a sequence or a range is implemented.".  Next, I revised the nomenclature as NG_009616.1:g.30012_32416delins[NG_052969.1:g.788322_791554], but, it came back with another error message "Position 791554 is out of range.".  I do not know how to resolve this problem.  Please kindly advise.

Your input is highly appreciated.

(NB: to investigate the nucleotide change in cDNA level, we amplified the BTK sequence using cDNA, and found out that the patient had skipping of exon 8,9,10).

Thank you.

Best regards,

Chai Teng, Chear

[J.F.J. Laros]

Dear Chai Teng Chear,

Thank you for using Mutalyzer.

The Name Checker in the current version of Mutalyzer does not support an
insertion of a slice of a different reference sequence. Furthermore, any
description that contains uncertainties can never be checked for correctness.

In this case, a syntactic check [1] is the only thing we can offer. It seems
that your description does pass that test.


With kind regards,
Jeroen.

References:
[1] https://mutalyzer.nl/syntax-checker?description=NG_009616.1%3Ag.30012_32416delins%5B%28302%29%3BNG_052969.1%3Ag.788322_791554%3BGT%5D

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Jeroen F.J. Laros - J.F.J...@lumc.nl

[Johan den Dunnen]

Dear Chai Teng Chear,

in addition to Jeroen's answer, based on current HGVS recommendations
your description
NG_009616.1:g.30012_32416delins[(302);NG_052969.1:g.788322_791554;GT] is
correct although, since you know the sequence of the 302 inserted
sequence, is has to be specified.

Since this gives a very long variant description the recommendation is
to submit the inserted sequence to a DNA database (e.g. GenBank). The
submission could include the sequence similar to that from a segment in
NG_052969.1 and the GT dinucleotide. When you have done so the
description would be like
NG_009616.1:g.30012_32416delins[REFSEQ.1:g....._....] where REFSEQ.1 is
the accession number you receive for the sequence file.

Another suggestion, the HGVS recommendation is to describe variants
based on a chromosomal reference sequence, so like
NC_000023.11:g.101358809_101361213delins[(302);NG_052969.1:g.788322_791554;GT].


Finally, DNA diagnostics is based on sharing data on genes, variants and
phenotypes. Without sharing DNA diagnostics would not be possible. When
we do not share, we do not offer optimal care to the patients and their
families. Please, in the interest of the patients and their families, do
not forget to submit your findings to the BTK gene variant database
immediately (check BTK.org to find a database). Important to realize,
even when the variants have been reported before: EVERY OBSERVATION
COUNTS !!

Yours sincerely,

Johan den Dunnen
HGVS/HVP/HUGO sequence variant description working group
http://www.HGVS.org/varnomen
facebook.com/HGVSmutnomen