X-150649761-G-C

Variant names:

• chrX-150649761-G-C
• rs587783861
• NM_000252.3:c.913G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000252.3(MTM1):​c.913G>C​(p.Glu305Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,782 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E305K) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: MTM1 NM_000252.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.96
• Publications: 5 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTM1	NM_000252.3	c.913G>C	p.Glu305Gln	missense_variant	Exon 10 of 15	ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7	c.913G>C	p.Glu305Gln	missense_variant	Exon 10 of 15	1	NM_000252.3	ENSP00000359423.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000548 AC: 1 AN: 182641 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096782 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 362258

African (AFR) AF: 0.00 AC: 0 AN: 26365

American (AMR) AF: 0.0000284 AC: 1 AN: 35150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19364

East Asian (EAS) AF: 0.00 AC: 0 AN: 30145

South Asian (SAS) AF: 0.00 AC: 0 AN: 53966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4124

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841093

Other (OTH) AF: 0.00 AC: 0 AN: 46051

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe X-linked myotubular myopathy Uncertain:1

Sep 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 305 of the MTM1 protein (p.Glu305Gln). This variant is present in population databases (rs587783861, gnomAD 0.004%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with MTM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1498542). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MTM1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		10
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.70
Sift	Benign	0.046	D
Sift4G	Benign	0.064	T
Vest4		0.79
ClinPred		0.82	D
GERP RS		5.0
Varity_R		0.71
gMVP		0.63
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587783861; hg19: chrX-149818234;