chrX-150659694-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS1_ModeratePM2PP3_Moderate

The NM_000252.3(MTM1):​c.1291G>A​(p.Asp431Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: not found (cov: 23)

Consequence

MTM1
NM_000252.3 missense

Scores

4
7
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 9.94
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PS1
Transcript NM_000252.3 (MTM1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.842

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MTM1NM_000252.3 linkc.1291G>A p.Asp431Asn missense_variant Exon 12 of 15 ENST00000370396.7 NP_000243.1 Q13496-1A0A024RC06

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MTM1ENST00000370396.7 linkc.1291G>A p.Asp431Asn missense_variant Exon 12 of 15 1 NM_000252.3 ENSP00000359423.3 Q13496-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:2
Apr 29, 2015
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The D431N variant in the MTM1 gene has been reported in a male patient affected with X-linked myotubular myopathy whose mother was noted to be a carrier (Laporte et al., 1997). The D431N variant was reported in cis with a second D433N variant, however the two missense variants are nearby and therefore would be considered as an insertion deletion alteration c.1291_1297delGATGCTGinsAATGCTA using alternate nomenclature. The D431N variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D431N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in a nearby residue (R421Q) has been reported in the Human Gene Mutation Database in association with X-linked recessive myotubular myopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. The D431N variant is a strong candidate for a disease-causing variant, however the possibility it may be a rare benign variant cannot be excluded -

May 16, 2017
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 23, 2017
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Asp431Asn variant in MTM1 has been reported in 1 male with X-linked recessive myotubular myopathy, who carried a second variant 2 amino acids downstream on the same allele (p.Asp433Asn; Laporte 1997). Please note, it is unclear if these two variants occurred independently or as a single event (p.Asp431_Asp433delinsAsnAlaAsn). Both variants were absent from large population studies. Computational prediction tools and conservation analyses suggest that the p.Asp431Asn variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Asp431Asn variant is uncertain. -

not specified Uncertain:1
May 22, 2017
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.44
BayesDel_addAF
Benign
-0.013
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.88
D
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D
M_CAP
Pathogenic
0.52
D
MetaRNN
Pathogenic
0.84
D
MetaSVM
Uncertain
0.60
D
MutationAssessor
Benign
1.5
L
PrimateAI
Uncertain
0.75
T
PROVEAN
Uncertain
-3.8
D
REVEL
Uncertain
0.48
Sift
Benign
0.036
D
Sift4G
Benign
0.062
T
Polyphen
0.58
P
Vest4
0.82
MutPred
0.25
Loss of ubiquitination at K427 (P = 0.0828);
MVP
0.96
MPC
1.6
ClinPred
0.99
D
GERP RS
5.5
Varity_R
0.56
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.21
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.21
Position offset: -30

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs886044782; hg19: chrX-149828167; COSMIC: COSV100080294; API