Variant nomenclature in CFTR

[Sriram Vaidyanathan]

Hello, 

We are attempting to submit a manuscript to the journal Genetics in Medicine. We have the following errors:

NC_000007.14(NM_000492.3):c.274-?_1585+?del (variantchecker): Offset +14041 from position 1585 is in downstream direction but should be in upstream direction. This is a known exon 4-10 deletion. Does mutalyzer support large deletions?

These variants seem to be legitimate but the recommended HGVS notation seems to be different. Is that accurate? In both cases, should it be changes to dupT instead of insT?

NM_000492.3(CFTR):c.3490_3491insT
(variantchecker): Insertion of T at position c.3490_3491 (g.3622_3623) was given, however, the HGVS notation prescribes that it should be a duplication of T at position c.3492 (g.3624).

NM_000492.3(CFTR): c.233_234insT
(variantchecker): Insertion of T at position c.233_234 (g.365_366) was given, however, the HGVS notation prescribes that it should be a duplication of T at position c.233 (g.365).

The following errors seem to indicate that the variants reported in the registry are mistaken. We can discuss how to handle this with the editor

NC_000007.14(NM_000492.3):c.3140-16A>G 
(variantchecker): A not found at position 117611565, found T instead.

NM_000492.3(CFTR):c.1837T>G
(variantchecker): T not found at position 1969, found G instead.

Thanks again for your input on handling these errors

Regards,

Sriram Vaidyanathan, PhD

Department of Pediatrics, Stanford University

[J.F.J. Laros]

Dear Sriram Vaidyanathan,

Thank you for using Mutalyzer.

The current version of Mutalyzer does not handle uncertainties in positions
(e.g., 274-? and 1585+?), so the first description is probably correct.

In the other cases, it seems that your input is indeed not fully compliant
with the HGVS variant nomenclature guidelines.


With kind regards,
Jeroen.

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

[Sriram Vaidyanathan]

Hello: This is a follow-up to the previous query based on reviewer comments. 

There are variants described as IVS17bTA and IVS8CA in datasets we obtained from registries. They refer to repeats in introns 17 and 8 respectively (10.1086/316940). We have been unable to find an HGVS compliant name for these variants. 

Secondly, there is a variant named NM_000492.3(CFTR):c.1408A>G. I receive the following error 

(variantchecker): A not found at position 1540, found G instead.

This refers to a well-characterized benign variant described as p.M470V. I tried the back converter function and I received the following message. 

M not found at position 470, found V instead

Does it mean that V has been established to be the more common amino acid in that position? 

Thanks again for your help! 

Best regards, 

Sriram

[J.F.J. Laros]

Dear Sriram,

> There are variants described as IVS17bTA and IVS8CA in datasets we obtained
> from registries.

These descriptions can not be interpreted because positions are missing.
Please see these [1,2] document for more information.

> Secondly, there is a variant named NM_000492.3(CFTR):c.1408A>G. I receive
> the following error
>
> (variantchecker): A not found at position 1540, found G instead.

It seems that the reference sequence has been changed after this description
was submitted, the following description (using an older reference
sequence) seems to work fine.

NM_000492.2:c.1408A>G

I hope this helps.


With kind regards,
Jeroen.

References:
[1] https://varnomen.hgvs.org/history-1996.html
[2] https://varnomen.hgvs.org/bg-material/numbering/

[Sriram Vaidyanathan]

Hello: This is a follow up to the previous query. We were recently informed that the most recent genomic reference to use for CFTR is 
NM_000492.4. This works perfectly fine for SNPs. However, I get an error when I enter the following for splicing mutations:

NC_000007.14(NM_000492.4):c.164+1G>T

The error says "NM_000492.4 is not annotated on NC_000007.14." I don't receive any error if I enter - NC_000007.14(NM_000492.3):c.164+1G>T Do we continue to use NM_000492.3 for these mutations?  Thanks again for your help

Best regards, 

Sriram

[J.F.J. Laros]

Dear Sriram,

The chromosomal reference file on the Mutalyzer 2 server is out of date.
On one hand this is inconvenient for those who want to use newer annotations,
on the other hand people expect that when a description passes the HGVS
check, it will also do so in the future. This is a bit of a dilemma.

In this case, you can use Mutalyzer 3 [1] as it uses a newer version of the
chromosomal reference file. You will however run into the same problem
eventually.

The only real solution would be for the NCBI to provide not only the latest,
but also all previous annotations.

With kind regards,
Jeroen.

References:

[1] https://v3.mutalyzer.nl

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