NM_000252.3:c.1260+5G>A

Variant names:

• chrX-150658032-G-A
• rs587783769
• NM_000252.3:c.1260+5G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000252.3(MTM1):​c.1260+5G>A variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene MTM1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 24)
• Consequence: MTM1 NM_000252.3 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.17
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P, Myriad Women’s Health, Ambry Genetics

ACMG classification

Specifications for MTM1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-150658032-G-A is Pathogenic according to our data. Variant chrX-150658032-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158911.

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.1260+5G>A		splice_region intron	N/A	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.1260+5G>A		splice_region intron	N/A	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.1260+5G>A		splice_region intron	N/A	NP_001363835.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	ENST00000370396.7	TSL:1 MANE Select	c.1260+5G>A		splice_region intron	N/A	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000689314.1		c.1305+5G>A		splice_region intron	N/A	ENSP00000510607.1	A0A8I5KZ76
	MTM1	ENST00000866458.1		c.1305+5G>A		splice_region intron	N/A	ENSP00000536517.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	30
DANN	Benign	0.87
PhyloP100		5.2
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.71		Position offset: -47
DS_DL_spliceai		0.98		Position offset: -5

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

Other links and lift over

dbSNP: rs587783769; hg19: chrX-149826505;