X-150592616-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_000252.3(MTM1):c.2T>C(p.Met1?) variant causes a start lost change. 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 (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: MTM1 NM_000252.3 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.22

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.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000252.3 (MTM1) was described as [Pathogenic] in ClinVar as 158969
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-150592616-T-C is Pathogenic according to our data. Variant chrX-150592616-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1966402.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTM1	NM_000252.3	c.2T>C	p.Met1?	start_lost	2/15	ENST00000370396.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTM1	ENST00000370396.7	c.2T>C	p.Met1?	start_lost	2/15	1	NM_000252.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 30, 2022

Disruption of the initiator codon has been observed in individual(s) with clinical features of MTM1-related conditions (PMID: 11793470, 12522554, 22968136, 30902907). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the MTM1 mRNA. The next in-frame methionine is located at codon 96. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.70
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.38	T;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.53	D
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.62
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.0020	B;.
Vest4		0.91
MutPred		0.97		Gain of glycosylation at M1 (P = 0.0237);Gain of glycosylation at M1 (P = 0.0237);
MVP		1.0
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.74
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-149761078;