chrX-150614696-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7BA1BP4

This summary comes from the ClinGen Evidence Repository: The variant NM_000252.3:c.339T>C in MTM1 is a synonymous (silent) variant (p.Cys113=). The highest population filtering allele frequency in gnomAD v4.1.0 is 0.003242 (198/54107 alleles, 58 hemizygotes) in African/African American population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.000016) for BA1, and therefore meets this criterion (BA1). In addition, SpliceAI does not predict impact to splicing, and the variant occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). In summary, this variant meets the criteria to be classified as benign for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4, BP7. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10539080/MONDO:0018947/149

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., 36 hem., cov: 22)

Exomes 𝑓: 0.00014 ( 0 hom. 32 hem. )

Consequence

MTM1
NM_000252.3 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:6

Conservation

PhyloP100: 2.27

Publications

0 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

For more information check the summary or visit ClinGen Evidence Repository.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTM1	NM_000252.3 link	c.339T>C	p.Cys113Cys	synonymous_variant	Exon 5 of 15	ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7 link	c.339T>C	p.Cys113Cys	synonymous_variant	Exon 5 of 15	1	NM_000252.3	ENSP00000359423.3

Frequencies

GnomAD3 genomes

AF:

0.000999

AC:

111

AN:

111075

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000575

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00134

GnomAD2 exomes

AF:

0.000349

AC:

AN:

171830

AF XY:

0.000240

show subpopulations

Gnomad AFR exome

AF:

0.00381

Gnomad AMR exome

AF:

0.000447

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:

0.000233

GnomAD4 exome

AF:

0.000138

AC:

131

AN:

947186

Hom.:

Cov.:

AF XY:

0.000123

AC XY:

AN XY:

259486

show subpopulations

African (AFR)

AF:

0.00403

AC:

AN:

23558

American (AMR)

AF:

0.000547

AC:

AN:

34757

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18313

East Asian (EAS)

AF:

0.00

AC:

AN:

29327

South Asian (SAS)

AF:

0.00

AC:

AN:

50097

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40089

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3793

European-Non Finnish (NFE)

AF:

0.00000708

AC:

AN:

706023

Other (OTH)

AF:

0.000291

AC:

AN:

41229

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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

AF:

0.000999

AC:

111

AN:

111129

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

AN XY:

33349

show subpopulations

African (AFR)

AF:

0.00337

AC:

103

AN:

30549

American (AMR)

AF:

0.000575

AC:

AN:

10440

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2638

East Asian (EAS)

AF:

0.00

AC:

AN:

3561

South Asian (SAS)

AF:

0.00

AC:

AN:

2624

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5949

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52958

Other (OTH)

AF:

0.00132

AC:

AN:

1510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000996

Hom.:

Bravo

AF:

0.00133

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 29, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:1

Dec 24, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Severe X-linked myotubular myopathy

Benign:1

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Centronuclear myopathy

Benign:1

Aug 07, 2024

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The variant NM_000252.3:c.339T>C in MTM1 is a synonymous (silent) variant (p.Cys113=). The highest population filtering allele frequency in gnomAD v4.1.0 is 0.003242 (198/54107 alleles, 58 hemizygotes) in African/African American population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.000016) for BA1, and therefore meets this criterion (BA1). In addition, SpliceAI does not predict impact to splicing, and the variant occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). In summary, this variant meets the criteria to be classified as benign for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4, BP7. (Congenital Myopathies VCEP specifications version 1; 8/7/2024)

MTM1-related disorder

Benign:1

Nov 14, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.68

PhyloP100

2.3

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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