rs587783784

Positions:

• chrX-150598585-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.137-7T>G variant in MTM1 is located in the 3’ non-canonical splice site of intron 3. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor Splice AI gives a score of 0.55, which is above the threshold of 0.5, suggesting impact on splicing (PP3). In summary, this variant meets the criteria to be classified as uncertain significance for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM2_Supporting, PP3. (Congenital Myopathies VCEP specifications Version 1: 8/7/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA271794/MONDO:0018947/149

• Frequency: Genomes: not found (cov: 23)
• Consequence: MTM1 NM_000252.3 splice_region, intron
• Scores: Splicing: ADA: 0.9359
• Clinical Significance: Uncertain significance reviewed by expert panel U:3
• Conservation: PhyloP100: 3.84

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTM1	NM_000252.3	c.137-7T>G		splice_region_variant, intron_variant		ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7	c.137-7T>G		splice_region_variant, intron_variant		1	NM_000252.3	ENSP00000359423.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 19

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Severe X-linked myotubular myopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 15, 2019	This sequence change falls in intron 3 of the MTM1 gene. It does not directly change the encoded amino acid sequence of the MTM1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with myotubular myopathy (PMID: 11793470). ClinVar contains an entry for this variant (Variation ID: 158926). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 11793470). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 29, 2013	- -

Centronuclear myopathy Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Aug 07, 2024

The c.137-7T>G variant in MTM1 is located in the 3’ non-canonical splice site of intron 3. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor Splice AI gives a score of 0.55, which is above the threshold of 0.5, suggesting impact on splicing (PP3). In summary, this variant meets the criteria to be classified as uncertain significance for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM2_Supporting, PP3. (Congenital Myopathies VCEP specifications Version 1: 8/7/2024). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Pathogenic	0.73
SpliceAI score (max)		0.55		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -15
DS_AL_spliceai		0.55		Position offset: 7

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

Publications

LitVar

Other links and lift over

dbSNP: rs587783784; hg19: chrX-149767049;