rs587783807

Variant names:

• chrX-150671485-A-G
• rs587783807
• NM_000252.3:c.1702A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.1702A>G variant in MTM1 is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 568. The highest population filtering allele frequency in gnomAD v4.1.0 is 0.00002629 (33/895101 alleles, 9 hemizygotes) in European (non-Finnish) population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.000016) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.212, which is neither above nor below the thresholds predicting a damaging or benign impact on MTM1 function. In summary, this variant meets the criteria to be classified as benign for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA172597/MONDO:0018947/149

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000030 (0 hom. 9 hem.)
• Consequence: MTM1 NM_000252.3 missense
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: 1.60
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P, Myriad Women’s Health, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.1702A>G	p.Ile568Val	missense	Exon 15 of 15	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.1702A>G	p.Ile568Val	missense	Exon 15 of 15	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.1699A>G	p.Ile567Val	missense	Exon 15 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.1702A>G	p.Ile568Val	missense	Exon 15 of 15	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000689314.1		c.1747A>G	p.Ile583Val	missense	Exon 16 of 16	ENSP00000510607.1	A0A8I5KZ76
	MTM1	ENST00000866458.1		c.1747A>G	p.Ile583Val	missense	Exon 16 of 16	ENSP00000536517.1

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 110829 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000377

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000491 AC: 9 AN: 183296 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000978

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 33 AN: 1098164 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 9 AN XY: 363526

African (AFR) AF: 0.0000379 AC: 1 AN: 26396

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.0000368 AC: 31 AN: 842086

Other (OTH) AF: 0.0000217 AC: 1 AN: 46097

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 110829 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 32995

African (AFR) AF: 0.00 AC: 0 AN: 30413

American (AMR) AF: 0.00 AC: 0 AN: 10367

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3548

South Asian (SAS) AF: 0.00 AC: 0 AN: 2610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000377 AC: 2 AN: 53015

Other (OTH) AF: 0.00 AC: 0 AN: 1480

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Centronuclear myopathy (1)
-	-	1	not specified (1)
-	-	1	Severe X-linked myotubular myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Benign	0.38
DEOGEN2	Benign	0.29	T
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.40	N
PhyloP100		1.6
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.21
Sift	Benign	0.56	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.040
MutPred		0.23		Gain of methylation at K569 (P = 0.1314)
MVP		0.73
MPC		0.52
ClinPred		0.035	T
GERP RS		3.7
Varity_R		0.066
gMVP		0.33
Mutation Taster		=96/4	polymorphism

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: rs587783807; hg19: chrX-149839958;