chrX-150596499-C-T

Variant names:

• chrX-150596499-C-T
• rs781886721
• NM_000252.3:c.65C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000252.3(MTM1):​c.65C>T​(p.Thr22Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000824 in 1,091,784 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T22T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 2 hem.)
• Consequence: MTM1 NM_000252.3 missense, splice_region
• Scores: Splicing: ADA: 0.00009593
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.569
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.122770846).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

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.65C>T	p.Thr22Met	missense splice_region	Exon 3 of 15	NP_000243.1
	MTM1	NM_001376908.1		c.65C>T	p.Thr22Met	missense splice_region	Exon 3 of 15	NP_001363837.1
	MTM1	NM_001376906.1		c.65C>T	p.Thr22Met	missense splice_region	Exon 3 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.65C>T	p.Thr22Met	missense splice_region	Exon 3 of 15	ENSP00000359423.3
	MTM1	ENST00000689314.1		c.65C>T	p.Thr22Met	missense splice_region	Exon 3 of 16	ENSP00000510607.1
	MTM1	ENST00000866458.1		c.65C>T	p.Thr22Met	missense splice_region	Exon 3 of 16	ENSP00000536517.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000547 AC: 1 AN: 182840 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000824 AC: 9 AN: 1091784 Hom.: 0 Cov.: 28 AF XY: 0.00000558 AC XY: 2 AN XY: 358254

African (AFR) AF: 0.00 AC: 0 AN: 26254

American (AMR) AF: 0.00 AC: 0 AN: 35173

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19329

East Asian (EAS) AF: 0.00 AC: 0 AN: 30161

South Asian (SAS) AF: 0.0000741 AC: 4 AN: 53984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40433

Middle Eastern (MID) AF: 0.000308 AC: 1 AN: 3248

European-Non Finnish (NFE) AF: 0.00000478 AC: 4 AN: 837393

Other (OTH) AF: 0.00 AC: 0 AN: 45809

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	10
DANN	Benign	0.95
DEOGEN2	Benign	0.40	T
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.6	L
PhyloP100		0.57
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.21
Sift	Uncertain	0.026	D
Sift4G	Benign	0.067	T
Polyphen		0.34	B
Vest4		0.14
MutPred		0.24		Loss of phosphorylation at T22 (P = 0.0073)
MVP		0.68
MPC		0.65
ClinPred		0.055	T
GERP RS		2.4
Varity_R		0.027
gMVP		0.70
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000096
dbscSNV1_RF	Benign	0.0
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: rs781886721; hg19: chrX-149764963;