rs587783784

Variant names:

• chrX-150598585-T-G
• rs587783784
• NM_000252.3:c.137-7T>G

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	NM_000252.3	MANE Select	c.137-7T>G		splice_region intron	N/A	NP_000243.1
	MTM1	NM_001376908.1		c.137-7T>G		splice_region intron	N/A	NP_001363837.1
	MTM1	NM_001376906.1		c.137-7T>G		splice_region intron	N/A	NP_001363835.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	ENST00000370396.7	TSL:1 MANE Select	c.137-7T>G		splice_region intron	N/A	ENSP00000359423.3
	MTM1	ENST00000689314.1		c.137-7T>G		splice_region intron	N/A	ENSP00000510607.1
	MTM1	ENST00000685944.1		c.137-7T>G		splice_region intron	N/A	ENSP00000509266.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 19

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	Severe X-linked myotubular myopathy (2)
-	1	-	Centronuclear myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Benign	0.95
PhyloP100		3.8

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

Other links and lift over

dbSNP: rs587783784; hg19: chrX-149767049;