rs587783818

Variant names:

• chrX-150614658-A-G
• rs587783818
• NM_000252.3:c.301A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_000252.3(MTM1):​c.301A>G​(p.Ser101Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. S101R) has been classified as Uncertain significance. The gene MTM1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 22)
• Consequence: MTM1 NM_000252.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.66
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P, Myriad Women’s Health, Ambry Genetics

ACMG classification

Specifications for MTM1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• 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-150614658-A-G is Pathogenic according to our data. Variant chrX-150614658-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158964.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	NM_000252.3	MANE Select	c.301A>G	p.Ser101Gly	missense	Exon 5 of 15	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.301A>G	p.Ser101Gly	missense	Exon 5 of 15	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.301A>G	p.Ser101Gly	missense	Exon 5 of 15	NP_001363835.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	ENST00000370396.7	TSL:1 MANE Select	c.301A>G	p.Ser101Gly	missense	Exon 5 of 15	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000689314.1		c.346A>G	p.Ser116Gly	missense	Exon 6 of 16	ENSP00000510607.1	A0A8I5KZ76
	MTM1	ENST00000866458.1		c.346A>G	p.Ser116Gly	missense	Exon 6 of 16	ENSP00000536517.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Severe X-linked myotubular myopathy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	-0.00040	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.034	D
Polyphen		0.087	B
Vest4		0.71
MutPred		0.26		Loss of phosphorylation at S101 (P = 0.0255)
MVP		0.94
MPC		1.5
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.85
gMVP		0.86
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.67		Position offset: 0

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

Other links and lift over

dbSNP: rs587783818; hg19: chrX-149783131;