rs1557413092

Variant names:

• chrX-150614700-G-A
• rs1557413092
• NM_000252.3:c.342+1G>A

Variant summary

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

The NM_000252.3(MTM1):​c.342+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MTM1 NM_000252.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.30
• 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.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06125828 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-150614700-G-A is Pathogenic according to our data. Variant chrX-150614700-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 435903.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	NM_000252.3	MANE Select	c.342+1G>A		splice_donor intron	N/A	NP_000243.1
	MTM1	NM_001376908.1		c.342+1G>A		splice_donor intron	N/A	NP_001363837.1
	MTM1	NM_001376906.1		c.342+1G>A		splice_donor 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.342+1G>A		splice_donor intron	N/A	ENSP00000359423.3
	MTM1	ENST00000689314.1		c.387+1G>A		splice_donor intron	N/A	ENSP00000510607.1
	MTM1	ENST00000685944.1		c.342+1G>A		splice_donor intron	N/A	ENSP00000509266.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 925193 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 247171

African (AFR) AF: 0.00 AC: 0 AN: 23107

American (AMR) AF: 0.00 AC: 0 AN: 34648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18171

East Asian (EAS) AF: 0.00 AC: 0 AN: 29177

South Asian (SAS) AF: 0.00 AC: 0 AN: 49577

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39967

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3741

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 686443

Other (OTH) AF: 0.00 AC: 0 AN: 40362

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:1

May 25, 2017

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	33
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		9.3
GERP RS		5.2
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.96		Position offset: -1

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

Other links and lift over

dbSNP: rs1557413092; hg19: chrX-149783173;