X-150614588-G-C

Variant names:

• chrX-150614588-G-C
• rs587783812
• NM_000252.3:c.232-1G>C

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.232-1G>C variant causes a splice acceptor, 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)
• Consequence: MTM1 NM_000252.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.25
• 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. Cryptic splice site detected, with MaxEntScore 4.8, offset of -33, new splice context is: tgttttaattatactgacAGaaa. 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-150614588-G-C is Pathogenic according to our data. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614588-G-C is described in CliVar as Pathogenic. Clinvar id is 3235226.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTM1	NM_000252.3	c.232-1G>C		splice_acceptor_variant, intron_variant	Intron 4 of 14	ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7	c.232-1G>C		splice_acceptor_variant, intron_variant	Intron 4 of 14	1	NM_000252.3	ENSP00000359423.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 21

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

Feb 16, 2022

MVZ Medizinische Genetik Mainz

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PVS1, PS1_SUP, PM2_SUP (ACMG Version 3) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	28
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		7.3
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs587783812; hg19: chrX-149783061;