X-150671507-A-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_000252.3(MTM1):​c.1724A>G​(p.Gln575Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,208,938 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign 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. Q575H) has been classified as Uncertain significance. The gene MTM1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000011 (0 hom. 4 hem.)
• Consequence: MTM1 NM_000252.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• 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: 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35289115).
• BS2: High Hemizygotes in GnomAdExome4 at 4 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.1724A>G	p.Gln575Arg	missense	Exon 15 of 15	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.1724A>G	p.Gln575Arg	missense	Exon 15 of 15	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.1721A>G	p.Gln574Arg	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.1724A>G	p.Gln575Arg	missense	Exon 15 of 15	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000689314.1		c.1769A>G	p.Gln590Arg	missense	Exon 16 of 16	ENSP00000510607.1	A0A8I5KZ76
	MTM1	ENST00000866458.1		c.1769A>G	p.Gln590Arg	missense	Exon 16 of 16	ENSP00000536517.1

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 110870 Hom.: 0 Cov.: 22

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

GnomAD4 exome AF: 0.0000109 AC: 12 AN: 1098068 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 4 AN XY: 363432

African (AFR) AF: 0.0000379 AC: 1 AN: 26397

American (AMR) AF: 0.00 AC: 0 AN: 35203

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54145

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40478

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

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 842023

Other (OTH) AF: 0.0000217 AC: 1 AN: 46094

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 110870 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33060

African (AFR) AF: 0.00 AC: 0 AN: 30431

American (AMR) AF: 0.00 AC: 0 AN: 10349

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2637

East Asian (EAS) AF: 0.00 AC: 0 AN: 3543

South Asian (SAS) AF: 0.00 AC: 0 AN: 2615

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5844

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

European-Non Finnish (NFE) AF: 0.0000377 AC: 2 AN: 53047

Other (OTH) AF: 0.00 AC: 0 AN: 1482

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Severe X-linked myotubular myopathy (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	1.9	L
PhyloP100		8.2
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.41
Sift	Benign	0.32	T
Sift4G	Benign	0.27	T
Polyphen		0.0050	B
Vest4		0.33
MVP		0.99
MPC		0.87
ClinPred		0.87	D
GERP RS		4.8
Varity_R		0.47
gMVP		0.70
Mutation Taster		=70/30	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: rs1347335331; hg19: chrX-149839980;