rs587783781

Variant names:

• chrX-150659756-G-A
• rs587783781
• NM_000252.3:c.1353G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM6 PP3 PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000252.3:c.1353G>A variant in MTM1 is a synonymous variant (p.Gln451=) located near the canonical donor site of intron 12. The variant is absent from gnomAD v4.1.0 meeting PM2_Supporting. The silent variant is predicted to impact splicing by SpliceAI (PP3). This variant has been reported in at least three probands, one with myotubular myopathy, one with congenital myopathy and abnormal muscle biopsy, and another with neonatal hypotonia. One of the three was a de novo occurrence with unconfirmed parental relationships (PS4_Moderate, PM6; PMID:10790201; LabCorp, ClinVar: SCV001391223.5). In summary, the variant meets the criteria to be classified as likely pathogenic for X-linked centronuclear myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PS4_Moderate, PM6, PM2_Supporting, PP3 (ClinGen Congenital Myopathies VCEP specifications version 1.0.0; 1/13/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA271787/MONDO:0018947/149

• Frequency: Genomes: not found (cov: 23)
• Consequence: MTM1 NM_000252.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.9640
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 6.83
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	NM_000252.3	MANE Select	c.1353G>A	p.Gln451Gln	splice_region synonymous	Exon 12 of 15	NP_000243.1
	MTM1	NM_001376908.1		c.1353G>A	p.Gln451Gln	splice_region synonymous	Exon 12 of 15	NP_001363837.1
	MTM1	NM_001376906.1		c.1353G>A	p.Gln451Gln	splice_region synonymous	Exon 12 of 15	NP_001363835.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	ENST00000370396.7	TSL:1 MANE Select	c.1353G>A	p.Gln451Gln	splice_region synonymous	Exon 12 of 15	ENSP00000359423.3
	MTM1	ENST00000689314.1		c.1398G>A	p.Gln466Gln	splice_region synonymous	Exon 13 of 16	ENSP00000510607.1
	MTM1	ENST00000866458.1		c.1398G>A	p.Gln466Gln	splice_region synonymous	Exon 13 of 16	ENSP00000536517.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Benign	0.92
PhyloP100		6.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.87		Position offset: 0

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

Other links and lift over

dbSNP: rs587783781; hg19: chrX-149828229;