rs587783826
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000252.3(MTM1):c.431del(p.Leu144ArgfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L144L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 22)
Consequence
MTM1
NM_000252.3 frameshift
NM_000252.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.15
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 Pathogenic. Variant got 18 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-150619125-CT-C is Pathogenic according to our data. Variant chrX-150619125-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 158972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150619125-CT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MTM1 | NM_000252.3 | c.431del | p.Leu144ArgfsTer11 | frameshift_variant | 6/15 | ENST00000370396.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MTM1 | ENST00000370396.7 | c.431del | p.Leu144ArgfsTer11 | frameshift_variant | 6/15 | 1 | NM_000252.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Severe X-linked myotubular myopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 25, 2017 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MTM1 are known to be pathogenic (PMID: 9305655, 10063835). This variant has been identified in individuals affected with X-linked myotubular myopathy (PMID: 20500434). ClinVar contains an entry for this variant (Variation ID: 158972). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu144Argfs*11) in the MTM1 gene. It is expected to result in an absent or disrupted protein product. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at