Need help to understand mutalyzer variant desciption

Question

[Titus]

He there ,

I was checking my cDNA annotation (annotates by VEP ) on web and i agreed in lot of point with mutalyser until this example concerning this variant NM_000249.3:c.1484delC ( https://mutalyzer.nl/name-checker?description=NM_000249.3%3Ac.1484delC ) (with genomic position on hg19 : chr3-37070348) :

Can someone explain to me why it's write :

Raw variant 1: deletion of 1682

or my variant is in position c.1484 ?

same for this

NM_000249.3(MLH1_v001):c.1489del

my variant is in c.1484 and not c.1489 ? To me c.1484 is the result of Left Align processing isn't it ? I checked in gnomAD : http://gnomad.broadinstitute.org/variant/3-37070348-AC-A .

I'm confused with this no coherent results.

Best

Answer 1

[jfjlaros]

The position referred to in the section Overview of the raw variants is relative to the start of the reference sequence (in this case this coincides with the transcription start since the reference sequence used is that of a transcript), not to the start of the CDS.

I hope this helps.

[Titus]

ok so that make sens, and at the end this link : https://mutalyzer.nl/name-checker?description=NM_001258271.1%3Ac.1484delC work because CDS for position 1484 are the same between the 2 NM.

Thank you for the answer it help :)

Do you have an idea for the second part of the question ?

Best

[jfjlaros]

Both variant descriptions (c.1484del and c.1489del) remove one C in a poly-C stretch. According to the HGVS 3' rule, which Mutalyzer follows, the last one is correct.

For the 3' rule, see: http://varnomen.hgvs.org/recommendations/general/

Does this answer your question?

[Titus]

Ok my bad you right. Thank you

Answer 2

[Emily]

Different transcripts of the same gene. NM_000249.3:c.1484delC is NM_001258271.1:c1682delC. Check the output, but I'm guessing they've changed your reference transcript. There may be something in their docs explaining why they've done this.

[Titus]

Thank you Emily,

I got an error with https://mutalyzer.nl/name-checker?description=NM_001258271.1%3Ac.1682delC so i looked to https://mutalyzer.nl/name-checker?description=NM_001258271.1%3Ac.1682del and it works but if i look the genomic region it's not the same (no presence of the poly C). I saw differences between length and number of the 2 transcripts but it seems the conversion is wrong isn’t ?