rs222410

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBP6_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:14O:1

Conservation

PhyloP100: 2.06

Publications

14 publications found

Variant links:

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

MTM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 92669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTM1	NM_000252.3 link	c.1260+3G>A		splice_region_variant, intron_variant	Intron 11 of 14	ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7 link	c.1260+3G>A		splice_region_variant, intron_variant	Intron 11 of 14	1	NM_000252.3	ENSP00000359423.3

Frequencies

GnomAD3 genomes

AF:

0.620

AC:

68859

AN:

111000

Hom.:

16256

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.556

AC:

99275

AN:

178634

AF XY:

0.563

show subpopulations

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 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.:

AF XY:

0.524

AC XY:

182777

AN XY:

348948

show subpopulations

African (AFR)

AF:

0.900

AC:

23540

AN:

26160

American (AMR)

AF:

0.606

AC:

21233

AN:

35024

Ashkenazi Jewish (ASJ)

AF:

0.605

AC:

11654

AN:

19274

East Asian (EAS)

AF:

0.295

AC:

8885

AN:

30100

South Asian (SAS)

AF:

0.712

AC:

38256

AN:

53764

European-Finnish (FIN)

AF:

0.463

AC:

18695

AN:

40350

Middle Eastern (MID)

AF:

0.682

AC:

2793

AN:

4095

European-Non Finnish (NFE)

AF:

0.490

AC:

404871

AN:

826936

Other (OTH)

AF:

0.538

AC:

24532

AN:

45559

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

8323

16646

24969

33292

41615

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13280

26560

39840

53120

66400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.621

AC:

68909

AN:

111051

Hom.:

16253

Cov.:

AF XY:

0.619

AC XY:

20585

AN XY:

33261

show subpopulations

African (AFR)

AF:

0.884

AC:

27090

AN:

30642

American (AMR)

AF:

0.671

AC:

7007

AN:

10443

Ashkenazi Jewish (ASJ)

AF:

0.601

AC:

1585

AN:

2639

East Asian (EAS)

AF:

0.302

AC:

1072

AN:

3545

South Asian (SAS)

AF:

0.705

AC:

1885

AN:

2673

European-Finnish (FIN)

AF:

0.464

AC:

2699

AN:

5819

Middle Eastern (MID)

AF:

0.662

AC:

143

AN:

216

European-Non Finnish (NFE)

AF:

0.495

AC:

26155

AN:

52891

Other (OTH)

AF:

0.633

AC:

956

AN:

1511

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

834

1668

2503

3337

4171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

590

1180

1770

2360

2950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.564

Hom.:

24284

Bravo

AF:

0.644

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 10, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 04, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 22, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

Severe X-linked myotubular myopathy

Benign:5Other:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Inborn genetic diseases

Benign:1

Jun 22, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.72

PhyloP100

2.1

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over