chrX-150645870-A-AGG

Variant names:

• chrX-150645870-A-AGG
• rs797045721
• ENST00000370396.7:c.856_857insGG

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000252.3(MTM1):​c.867_867+1dupGG variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). The gene MTM1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 24)
• Consequence: MTM1 NM_000252.3 splice_donor, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.06
• 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 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.104304634 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.9, offset of 0 (no position change), new splice context is: gggGTgagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-150645870-A-AGG is Pathogenic according to our data. Variant chrX-150645870-A-AGG is described in ClinVar as Pathogenic. ClinVar VariationId is 211537.Status of the report is criteria_provided_single_submitter, 1 stars.

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.867_867+1dupGG		splice_donor intron	N/A	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.867_867+1dupGG		splice_donor intron	N/A	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.867_867+1dupGG		splice_donor 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.856_857insGG	p.Val286GlyfsTer21	frameshift	Exon 9 of 15	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000689314.1		c.901_902insGG	p.Val301GlyfsTer21	frameshift	Exon 10 of 16	ENSP00000510607.1	A0A8I5KZ76
	MTM1	ENST00000866458.1		c.901_902insGG	p.Val301GlyfsTer21	frameshift	Exon 10 of 16	ENSP00000536517.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs797045721; hg19: chrX-149814343;