NM_000252.3:c.1724A>C

Variant names:

• chrX-150671507-A-C
• rs1347335331
• NM_000252.3:c.1724A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000252.3(MTM1):​c.1724A>C​(p.Gln575Pro) 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. Q575R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: MTM1 NM_000252.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.22
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785

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.1724A>C	p.Gln575Pro	missense	Exon 15 of 15	NP_000243.1
	MTM1	NM_001376908.1		c.1724A>C	p.Gln575Pro	missense	Exon 15 of 15	NP_001363837.1
	MTM1	NM_001376906.1		c.1721A>C	p.Gln574Pro	missense	Exon 15 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.1724A>C	p.Gln575Pro	missense	Exon 15 of 15	ENSP00000359423.3
	MTM1	ENST00000689314.1		c.1769A>C	p.Gln590Pro	missense	Exon 16 of 16	ENSP00000510607.1
	MTM1	ENST00000685944.1		c.1724A>C	p.Gln575Pro	missense	Exon 15 of 15	ENSP00000509266.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe X-linked myotubular myopathy Uncertain:1

Jul 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 575 of the MTM1 protein (p.Gln575Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MTM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 566537). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0").

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		8.2
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.061	T
Polyphen		0.92	P
Vest4		0.49
MutPred		0.23		Loss of helix (P = 0.079)
MVP		0.99
MPC		1.4
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.90
gMVP		0.90
Mutation Taster		=36/64	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: rs1347335331; hg19: chrX-149839980;