rs782137551

Positions:

chrX-150660471-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The variant NM_000252.3:c.1454C>T in MTM1 is a missense variant predicted to cause substitution of alanine by valine at amino acid 485 (p.Ala485Val). The filtering allele frequency in gnomAD v4.1.0 is 0.0005657 (35/45691 alleles, 10 hemizygotes) for the Admixed American population, which is higher than the ClinGen congenital myopathy MTM1 threshold (≥0.000016) for BA1, and therefore meets this criterion (BA1). The REVEL computational prediction analysis tool produced a score of 0.221, which is neither above nor below the thresholds predicting a damaging or benign impact on MTM1 function. In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: BA1 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10539261/MONDO:0018947/149

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000037 ( 0 hom. 11 hem. )

Consequence

MTM1
ENST00000370396.7 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:3

Conservation

PhyloP100: -0.433

Variant links:

Genes affected

MTM1 (HGNC:7448): (myotubularin 1) This gene encodes a dual-specificity phosphatase that acts on both phosphotyrosine and phosphoserine. It is required for muscle cell differentiation and mutations in this gene have been identified as being responsible for X-linked myotubular myopathy. [provided by RefSeq, Jul 2008]

MTM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTM1	NM_000252.3 linkuse as main transcript	c.1454C>T	p.Ala485Val	missense_variant	13/15	ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7 linkuse as main transcript	c.1454C>T	p.Ala485Val	missense_variant	13/15	1	NM_000252.3	ENSP00000359423	P1	Q13496-1

Frequencies

GnomAD3 genomes

AF:

0.00000893

AC:

AN:

111926

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34138

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000950

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000192

AC:

AN:

182615

Hom.:

AF XY:

0.000119

AC XY:

AN XY:

67337

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000985

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00177

GnomAD4 exome

AF:

0.0000375

AC:

AN:

1067294

Hom.:

Cov.:

AF XY:

0.0000327

AC XY:

AN XY:

336600

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000967

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000491

Gnomad4 OTH exome

AF:

0.0000443

GnomAD4 genome

AF:

0.00000893

AC:

AN:

111926

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34138

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000950

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000425

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.000206

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 17, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Severe X-linked myotubular myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

- -

Centronuclear myopathy

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Aug 07, 2024

The variant NM_000252.3:c.1454C>T in MTM1 is a missense variant predicted to cause substitution of alanine by valine at amino acid 485 (p.Ala485Val). The filtering allele frequency in gnomAD v4.1.0 is 0.0005657 (35/45691 alleles, 10 hemizygotes) for the Admixed American population, which is higher than the ClinGen congenital myopathy MTM1 threshold (≥0.000016) for BA1, and therefore meets this criterion (BA1). The REVEL computational prediction analysis tool produced a score of 0.221, which is neither above nor below the thresholds predicting a damaging or benign impact on MTM1 function. In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: BA1 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.70

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.73

M_CAP

Pathogenic

0.59

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.76

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.65

REVEL

Benign

0.22

Sift

Benign

0.26

Sift4G

Benign

0.16

Polyphen

0.0

Vest4

0.17

MutPred

0.52

Gain of helix (P = 0.0696);

MVP

0.50

MPC

0.62

ClinPred

0.021

GERP RS

1.5

Varity_R

0.14

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over