rs587783832

Variant names:

• chrX-150641275-C-A
• rs587783832
• NM_000252.3:c.535C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-150641275-C-A
• chrX-150641275-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000252.3(MTM1):​c.535C>A​(p.Pro179Thr) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P179S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: MTM1 NM_000252.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46
• Publications: 7 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 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000252.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-150641275-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 158978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915

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.535C>A	p.Pro179Thr	missense	Exon 8 of 15	NP_000243.1
	MTM1	NM_001376908.1		c.535C>A	p.Pro179Thr	missense	Exon 8 of 15	NP_001363837.1
	MTM1	NM_001376906.1		c.535C>A	p.Pro179Thr	missense	Exon 8 of 15	NP_001363835.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	ENST00000370396.7	TSL:1 MANE Select	c.535C>A	p.Pro179Thr	missense	Exon 8 of 15	ENSP00000359423.3
	MTM1	ENST00000689314.1		c.580C>A	p.Pro194Thr	missense	Exon 9 of 16	ENSP00000510607.1
	MTM1	ENST00000685944.1		c.535C>A	p.Pro179Thr	missense	Exon 8 of 15	ENSP00000509266.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		0.50	P
Vest4		0.84
MutPred		0.50		Gain of catalytic residue at P179 (P = 0.0399)
MVP		0.92
MPC		1.7
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.92
Mutation Taster		=20/80	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs587783832; hg19: chrX-149809748;