Genetic Variant MTM1:p.Thr495Ser (chrX-150663449-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1BS2

The NM_000252.3(MTM1):c.1484C>G(p.Thr495Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00001 in 1,097,289 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T495I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.000010 ( 0 hom. 2 hem. )

Consequence

MTM1
NM_000252.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.62

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

X-linked myotubular myopathy
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, Orphanet

MTM1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000252.3

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTM1	NM_000252.3 link	c.1484C>G	p.Thr495Ser	missense_variant	Exon 14 of 15	ENST00000370396.7	NP_000243.1	Q13496-1A0A024RC06

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7 link	c.1484C>G	p.Thr495Ser	missense_variant	Exon 14 of 15	1	NM_000252.3	ENSP00000359423.3		Q13496-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000548

AC:

AN:

182324

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1097289

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

362701

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26386

American (AMR)

AF:

0.00

AC:

AN:

35192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19363

East Asian (EAS)

AF:

0.00

AC:

AN:

30175

South Asian (SAS)

AF:

0.00

AC:

AN:

54098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40495

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4061

European-Non Finnish (NFE)

AF:

0.0000131

AC:

AN:

841468

Other (OTH)

AF:

0.00

AC:

AN:

46051

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.77

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.63

MetaSVM

Uncertain

0.70

MutationAssessor

Pathogenic

2.9

PhyloP100

4.6

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.65

Sift

Uncertain

0.023

Sift4G

Uncertain

0.039

Polyphen

0.35

Vest4

0.40

MutPred

0.71

Gain of disorder (P = 0.0418);

MVP

0.91

MPC

0.60

ClinPred

0.82

GERP RS

4.7

Varity_R

0.71

gMVP

0.82

Mutation Taster

=67/33

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over