rs797044504

Variant names:

• chrX-150663607-CAAGT-C
• rs797044504
• NM_000252.3:c.1644+3_1644+6delAAGT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The ENST00000370396.7(MTM1):​c.1643_1644+2delAAGT​(p.Gln548ArgfsTer13) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: MTM1 ENST00000370396.7 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.55
• 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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0933 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-150663607-CAAGT-C is Pathogenic according to our data. Variant chrX-150663607-CAAGT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 167309.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000370396.7. 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.1644+3_1644+6delAAGT		splice_region intron	N/A	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.1644+3_1644+6delAAGT		splice_region intron	N/A	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.1644+3_1644+6delAAGT		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.1643_1644+2delAAGT	p.Gln548ArgfsTer13	frameshift splice_donor splice_region intron	Exon 14 of 15	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000689314.1		c.1688_1689+2delAAGT	p.Gln563ArgfsTer13	frameshift splice_donor splice_region intron	Exon 15 of 16	ENSP00000510607.1	A0A8I5KZ76
	MTM1	ENST00000866458.1		c.1688_1689+2delAAGT	p.Gln563ArgfsTer13	frameshift splice_donor splice_region intron	Exon 15 of 16	ENSP00000536517.1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 2

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

Other links and lift over

dbSNP: rs797044504; hg19: chrX-149832080;