X-150641275-C-T

Position:

• chrX-150641275-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000252.3(MTM1):​c.535C>T​(p.Pro179Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P179T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: MTM1 NM_000252.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.46

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000252.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931
• PP5: Variant X-150641275-C-T is Pathogenic according to our data. Variant chrX-150641275-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 158978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150641275-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTM1	NM_000252.3	c.535C>T	p.Pro179Ser	missense_variant	8/15	ENST00000370396.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTM1	ENST00000370396.7	c.535C>T	p.Pro179Ser	missense_variant	8/15	1	NM_000252.3	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Centronuclear myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Mar 01, 2024

PS1+PM1+PM2+PP2+PP3+PP5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.025	D
Sift4G	Benign	0.13	T
Polyphen		0.50	P
Vest4		0.92
MutPred		0.64		Gain of disorder (P = 0.1218);
MVP		0.97
MPC		1.6
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.93

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

Other links and lift over

dbSNP: rs587783832; hg19: chrX-149809748; COSMIC: COSV105110373; COSMIC: COSV105110373;