[INQUIRY] Regarding Transcript NM_003494 versions

[Jae Ryu [AGTx]]

To Whom It May Concern,

I hope you are doing well today.

 

I have an inquiry regarding Transcript NM_003494 versions.

My sister-in-law had a dysf gene sequencing test at Invitae, Inc. and received a result below.

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DYSF / c.1464del (p.Gly489Glufs*4) / heterozygous / PATHOGENIC / NM_003494.3

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Because we don’t know what base is deleted on her gene from the result and the transcript version is different to other siblings’ results, we looked for the deleted base from NM_003494.3.

(Her siblings got tested in other country(South Korea), and their transcript versions are NM_003494.4)

After we looked at NM_003494.3 and NM_00.3494.4, We found that the deleted bases are different between my sister-in-law’s result and her siblings’ result.

 

her sibling’s results are below; her brother and two sisters have the same result below.

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DYSF c.1464delT (p.Gly489Glufs*4) / Het /           Pathogenic / NM_003494.4

DYSF c.2997G>T (p.Trp999Cys) / Het / Pathogenic / W999C

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If you see the results, you may see that the transcript versions are different: NM_003494.3 is for my sister-in-law and NM_003493.4 is for her siblings.

Thus, we look for 1464 position on each version, and we found base “A” at NM_003494.3 version and base “T” at NM_003494.4 version.

(We look for the reference for .3 version at https://www.ncbi.nlm.nih.gov/nuccore/NM_003494.3    / for .4 version at https://www.ncbi.nlm.nih.gov/nuccore/NM_003494 )

If you scroll down the page, you may see the full sequence data of NM_003494.x

 

With the comparison above, I sent an inquiry to Invitae, Inc. and received an answer below.

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The deleted nucleotide in your sister-in-law's DYSF gene is a "T" (so the deletion could also be written as c.1464delT, similar to her sibling's test result). We do not specify the sequence of deleted or duplicated nucleotides on our test reports to bring our nomenclature in line with HGVS (Human Genome Variation Society) recommendations, to reduce the chance of introducing errors through manual editing of variant names, and to make variant naming consistent across all deletions and duplications.

The transcript that we use, NM_003494.3, is an older version of NM_003494.4, but the two transcripts use the same reference sequence (NM_003494). The deleted nucleotide of your sister-in-law's DYSF gene can be confirmed by using a program called Mutalyzer: https://mutalyzer.nl/name-checker?description=NM_003494.3%3Ac.1464del.

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Although they answer that base “T” is deleted, the reference from NIH.gov shows different bases on the same position.

If their answer is correct, I believe that we must find the same Base on the same position, 1464 no matter what the version is, but bases are different on the same position by each version.

Because they use a program of your company, I think that you may resolve our question why 1464 position represents different bases by the different versions.

 

May you explain why I see the different bases by the versions?

Do I find a wrong information of NM_003494.3 from NIH.gov?

 

Please check and advise.

The weather is getting hot, please stay hydrated 😉

 

I appreciate your business.

 

[J.F.J. Laros]

Dear Jae Ryu,

The source of confusion is probably that "c." positions start counting from the
start of the coding sequence, not from the start of the transcript. In your case
c.1464 is at position 1840 of transcript NM_003494.3, while it is at position
1902 of transcript NM_003494.4.

When the variants are checked with Mutalyzer [1,2], they both delete a "T" and
the surrounding context is the same. So the descriptions seem to be correct.

I hope this helps.


With kind regards,
Jeroen.

References:
[1] https://mutalyzer.nl/name-checker?description=NM_003494.3%3Ac.1464del
[2] https://mutalyzer.nl/name-checker?description=NM_003494.4%3Ac.1464del

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