chrX-150659731-A-C

Variant names:

• chrX-150659731-A-C
• rs587783777
• NM_000252.3:c.1328A>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000252.3(MTM1):​c.1328A>C​(p.Asp443Ala) variant causes a missense 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. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. D443D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MTM1 NM_000252.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.27
• Publications: 1 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000252.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant X-150659731-A-C is Pathogenic according to our data. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150659731-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 158919.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.1328A>C	p.Asp443Ala	missense_variant	Exon 12 of 15	ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7	c.1328A>C	p.Asp443Ala	missense_variant	Exon 12 of 15	1	NM_000252.3	ENSP00000359423.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.80
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		9.3
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.79		Gain of catalytic residue at D443 (P = 0.077);
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587783777; hg19: chrX-149828204;