rs222410

Positions:

• chrX-150658030-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_000252.3(MTM1):​c.1260+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (16253 hom., 20585 hem., cov: 23)
  • Exomes 𝑓: 0.51 (97931 hom. 182777 hem.)
  • Failed GnomAD Quality Control
• Consequence: MTM1 NM_000252.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003382
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: 2.06

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant X-150658030-G-A is Benign according to our data. Variant chrX-150658030-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150658030-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTM1	NM_000252.3	c.1260+3G>A		splice_region_variant, intron_variant		ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7	c.1260+3G>A		splice_region_variant, intron_variant		1	NM_000252.3	ENSP00000359423.3

Frequencies

GnomAD3 genomes AF: 0.620 AC: 68859 AN: 111000 Hom.: 16256 Cov.: 23 AF XY: 0.618 AC XY: 20530 AN XY: 33200

Gnomad AFR AF: 0.884

Gnomad AMI AF: 0.472

Gnomad AMR AF: 0.671

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.705

Gnomad FIN AF: 0.464

Gnomad MID AF: 0.667

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.635

GnomAD3 exomes AF: 0.556 AC: 99275 AN: 178634 Hom.: 18466 AF XY: 0.563 AC XY: 36310 AN XY: 64502

Gnomad AFR exome AF: 0.897

Gnomad AMR exome AF: 0.592

Gnomad ASJ exome AF: 0.612

Gnomad EAS exome AF: 0.314

Gnomad SAS exome AF: 0.709

Gnomad FIN exome AF: 0.470

Gnomad NFE exome AF: 0.504

Gnomad OTH exome AF: 0.563

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.513 AC: 554459 AN: 1081262 Hom.: 97931 Cov.: 27 AF XY: 0.524 AC XY: 182777 AN XY: 348948

Gnomad4 AFR exome AF: 0.900

Gnomad4 AMR exome AF: 0.606

Gnomad4 ASJ exome AF: 0.605

Gnomad4 EAS exome AF: 0.295

Gnomad4 SAS exome AF: 0.712

Gnomad4 FIN exome AF: 0.463

Gnomad4 NFE exome AF: 0.490

Gnomad4 OTH exome AF: 0.538

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.621 AC: 68909 AN: 111051 Hom.: 16253 Cov.: 23 AF XY: 0.619 AC XY: 20585 AN XY: 33261

Gnomad4 AFR AF: 0.884

Gnomad4 AMR AF: 0.671

Gnomad4 ASJ AF: 0.601

Gnomad4 EAS AF: 0.302

Gnomad4 SAS AF: 0.705

Gnomad4 FIN AF: 0.464

Gnomad4 NFE AF: 0.495

Gnomad4 OTH AF: 0.633

Alfa AF: 0.549 Hom.: 16384

Bravo AF: 0.644

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.1260+3G>A in intron 11 of MTM1: This variant is not expected to have clinical significance because it has been identified in 49.9% (3355/6728) of European Ame rican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs222410). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Severe X-linked myotubular myopathy Benign:5 Other:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0040
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: rs222410; hg19: chrX-149826503; COSMIC: COSV60338291;