NM_000252.3:c.1234A>G

Variant names:

• chrX-150658001-A-G
• rs587783765
• NM_000252.3:c.1234A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000252.3(MTM1):​c.1234A>G​(p.Ile412Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I412L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MTM1 NM_000252.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 1.58
• Publications: 3 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 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000252.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-150658001-A-G is Pathogenic according to our data. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907. Variant chrX-150658001-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158907.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTM1	NM_000252.3	c.1234A>G	p.Ile412Val	missense_variant	Exon 11 of 15	ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7	c.1234A>G	p.Ile412Val	missense_variant	Exon 11 of 15	1	NM_000252.3	ENSP00000359423.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000293 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

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

- -

not provided Uncertain:1

Feb 21, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Reported heterozygous in female with centronuclear myopathy, however limited genes were evaluated and no X-inactivation studies were performed (Bevilacqua et al., 2009); This variant is associated with the following publications: (PMID: 24451234, 26995067, 30149909, 27017278, 19084976) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.68	D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.25
Sift	Benign	0.060	T
Sift4G	Benign	0.36	T
Polyphen		0.010	B
Vest4		0.23
MutPred		0.54		Loss of ubiquitination at K409 (P = 0.1231);
MVP		0.83
MPC		0.78
ClinPred		0.38	T
GERP RS		3.0
Varity_R		0.34
gMVP		0.51
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		1.0		Position offset: -1
DS_DL_spliceai		0.99		Position offset: 26

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

Other links and lift over

dbSNP: rs587783765; hg19: chrX-149826474;