rs781886721

Positions:

• chrX-150596499-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_000252.3(MTM1):​c.65C>T​(p.Thr22Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000824 in 1,091,784 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 2 hem.)
• Consequence: MTM1 NM_000252.3 missense, splice_region
• Scores: Splicing: ADA: 0.00009593
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.569

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.122770846).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00000824 (9/1091784) while in subpopulation MID AF= 0.000308 (1/3248). AF 95% confidence interval is 0.0000253. There are 0 homozygotes in gnomad4_exome. There are 2 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTM1	NM_000252.3	c.65C>T	p.Thr22Met	missense_variant, splice_region_variant	3/15	ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7	c.65C>T	p.Thr22Met	missense_variant, splice_region_variant	3/15	1	NM_000252.3	ENSP00000359423.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000547 AC: 1 AN: 182840 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67412

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 SAS exome AF: 0.0000527

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000824 AC: 9 AN: 1091784 Hom.: 0 Cov.: 28 AF XY: 0.00000558 AC XY: 2 AN XY: 358254

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000741

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000478

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Severe X-linked myotubular myopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 19, 2022	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 22 of the MTM1 protein (p.Thr22Met). This variant is present in population databases (rs781886721, gnomAD 0.005%). 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: 577570). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 20, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	10
DANN	Benign	0.95
DEOGEN2	Benign	0.40	T;.
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.50	T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.6	L;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.91	N;N
REVEL	Benign	0.21
Sift	Uncertain	0.026	D;D
Sift4G	Benign	0.067	T;D
Polyphen		0.34	B;.
Vest4		0.14
MutPred		0.24		Loss of phosphorylation at T22 (P = 0.0073);Loss of phosphorylation at T22 (P = 0.0073);
MVP		0.68
MPC		0.65
ClinPred		0.055	T
GERP RS		2.4
Varity_R		0.027
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000096
dbscSNV1_RF	Benign	0.0
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: rs781886721; hg19: chrX-149764963;