rs782137551

Variant names:

• chrX-150660471-C-T
• rs782137551
• NM_000252.3:c.1454C>T

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 variant NM_000252.3:c.1454C>T in MTM1 is a missense variant predicted to cause substitution of alanine by valine at amino acid 485 (p.Ala485Val). The filtering allele frequency in gnomAD v4.1.0 is 0.0005657 (35/45691 alleles, 10 hemizygotes) for the Admixed American population, which is higher than the ClinGen congenital myopathy MTM1 threshold (≥0.000016) for BA1, and therefore meets this criterion (BA1). The REVEL computational prediction analysis tool produced a score of 0.221, which is neither above nor below the thresholds predicting a damaging or benign impact on MTM1 function. In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: BA1 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10539261/MONDO:0018947/149

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000037 (0 hom. 11 hem.)
• Consequence: MTM1 NM_000252.3 missense
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: -0.433
• 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

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

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.1454C>T	p.Ala485Val	missense	Exon 13 of 15	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.1454C>T	p.Ala485Val	missense	Exon 13 of 15	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.1454C>T	p.Ala485Val	missense	Exon 13 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.1454C>T	p.Ala485Val	missense	Exon 13 of 15	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000689314.1		c.1499C>T	p.Ala500Val	missense	Exon 14 of 16	ENSP00000510607.1	A0A8I5KZ76
	MTM1	ENST00000866458.1		c.1499C>T	p.Ala500Val	missense	Exon 14 of 16	ENSP00000536517.1

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 111926 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000950

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000192 AC: 35 AN: 182615 AF XY: 0.000119

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000985

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.0000375 AC: 40 AN: 1067294 Hom.: 0 Cov.: 26 AF XY: 0.0000327 AC XY: 11 AN XY: 336600

African (AFR) AF: 0.00 AC: 0 AN: 25818

American (AMR) AF: 0.000967 AC: 34 AN: 35162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19179

East Asian (EAS) AF: 0.00 AC: 0 AN: 30069

South Asian (SAS) AF: 0.00 AC: 0 AN: 53445

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40411

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4026

European-Non Finnish (NFE) AF: 0.00000491 AC: 4 AN: 814085

Other (OTH) AF: 0.0000443 AC: 2 AN: 45099

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 111926 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34138

African (AFR) AF: 0.00 AC: 0 AN: 30790

American (AMR) AF: 0.0000950 AC: 1 AN: 10529

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3588

South Asian (SAS) AF: 0.00 AC: 0 AN: 2723

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6009

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53201

Other (OTH) AF: 0.00 AC: 0 AN: 1517

Alfa AF: 0.0000815 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.000206 AC: 25

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	0.076
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Uncertain	0.70	D
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.43
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.22
Sift	Benign	0.26	T
Sift4G	Benign	0.16	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.52		Gain of helix (P = 0.0696)
MVP		0.50
MPC		0.62
ClinPred		0.021	T
GERP RS		1.5
Varity_R		0.14
gMVP		0.50
Mutation Taster		=92/8	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: rs782137551; hg19: chrX-149828944; COSMIC: COSV99059540;