Genetic Variant MTM1:p.Cys113* (chrX-150614696-T-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000252.3(MTM1):c.339T>A(p.Cys113*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000106 in 947,188 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. C113C) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000011 ( 0 hom. 0 hem. )

Consequence

MTM1
NM_000252.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P, Myriad Women’s Health, Ambry Genetics

MTM1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-150614696-T-A is Pathogenic according to our data. Variant chrX-150614696-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1071778.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000252.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTM1	NM_000252.3	MANE Select	c.339T>A	p.Cys113*	stop_gained	Exon 5 of 15	NP_000243.1	Q13496-1
MTM1	NM_001376908.1		c.339T>A	p.Cys113*	stop_gained	Exon 5 of 15	NP_001363837.1	Q13496-1
MTM1	NM_001376906.1		c.339T>A	p.Cys113*	stop_gained	Exon 5 of 15	NP_001363835.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTM1	ENST00000370396.7	TSL:1 MANE Select	c.339T>A	p.Cys113*	stop_gained	Exon 5 of 15	ENSP00000359423.3	Q13496-1
MTM1	ENST00000689314.1		c.384T>A	p.Cys128*	stop_gained	Exon 6 of 16	ENSP00000510607.1	A0A8I5KZ76
MTM1	ENST00000866458.1		c.384T>A	p.Cys128*	stop_gained	Exon 6 of 16	ENSP00000536517.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000106

AC:

AN:

947188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

259488

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

23560

American (AMR)

AF:

0.00

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:

0.00000142

AC:

AN:

706023

Other (OTH)

AF:

0.00

AC:

AN:

41229

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

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>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Severe X-linked myotubular myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

FATHMM_MKL

Uncertain

0.85

PhyloP100

2.3

Vest4

0.97

GERP RS

4.1

Mutation Taster

=0/200

disease causing (fs/PTC)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over