rs587783765

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 4P and 6B. PM1PM5BP4_ModerateBS2

The NM_000252.3(MTM1):c.1234A>C(p.Ile412Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,208,237 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I412V) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

MTM1
NM_000252.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.58

Publications

3 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: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000252.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-150658001-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158907.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BP4

Computational evidence support a benign effect (MetaRNN=0.21505603).

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTM1	NM_000252.3 link	c.1234A>C	p.Ile412Leu	missense_variant	Exon 11 of 15	ENST00000370396.7	NP_000243.1	Q13496-1A0A024RC06

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7 link	c.1234A>C	p.Ile412Leu	missense_variant	Exon 11 of 15	1	NM_000252.3	ENSP00000359423.3		Q13496-1

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112221

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000190

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:

0.000665

GnomAD2 exomes

AF:

0.00000549

AC:

AN:

182221

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

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:

0.00

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1096016

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

361410

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26353

American (AMR)

AF:

0.0000284

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19370

East Asian (EAS)

AF:

0.00

AC:

AN:

30188

South Asian (SAS)

AF:

0.00

AC:

AN:

54064

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40495

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840197

Other (OTH)

AF:

0.0000217

AC:

AN:

46015

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112221

Hom.:

Cov.:

AF XY:

0.0000582

AC XY:

AN XY:

34371

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

30850

American (AMR)

AF:

0.000190

AC:

AN:

10552

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3600

South Asian (SAS)

AF:

0.00

AC:

AN:

2732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53287

Other (OTH)

AF:

0.000665

AC:

AN:

1503

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000604

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 11, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1234A>C (p.I412L) alteration is located in exon 11 (coding exon 10) of the MTM1 gene. This alteration results from a A to C substitution at nucleotide position 1234, causing the isoleucine (I) at amino acid position 412 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Severe X-linked myotubular myopathy

Uncertain:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 412 of the MTM1 protein (p.Ile412Leu). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with MTM1-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MTM1 protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.63

DEOGEN2

Uncertain

0.56

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.83

M_CAP

Benign

0.084

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.030

PhyloP100

1.6

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.63

REVEL

Benign

0.26

Sift

Benign

1.0

Sift4G

Benign

0.85

Polyphen

0.0

Vest4

0.39

MutPred

0.59

Loss of ubiquitination at K409 (P = 0.1079);

MVP

0.67

MPC

0.64

ClinPred

0.089

GERP RS

3.0

Varity_R

0.35

gMVP

0.79

Mutation Taster

=38/62

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over