rs140642341

Positions:

• chrX-150619117-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000252.3(MTM1):​c.422C>T​(p.Ala141Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000407 in 1,204,584 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 21 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A141P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000081 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.000037 (0 hom. 18 hem.)
• Consequence: MTM1 NM_000252.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 7.48

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant X-150619117-C-T is Benign according to our data. Variant chrX-150619117-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211534.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000807 (9/111542) while in subpopulation EAS AF= 0.000282 (1/3542). AF 95% confidence interval is 0.0000259. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTM1	NM_000252.3	c.422C>T	p.Ala141Val	missense_variant	6/15	ENST00000370396.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTM1	ENST00000370396.7	c.422C>T	p.Ala141Val	missense_variant	6/15	1	NM_000252.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000807 AC: 9 AN: 111487 Hom.: 0 Cov.: 23 AF XY: 0.0000891 AC XY: 3 AN XY: 33671

Gnomad AFR AF: 0.0000980

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000281

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.0000753

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000819 AC: 15 AN: 183221 Hom.: 0 AF XY: 0.000118 AC XY: 8 AN XY: 67753

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.000419

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000366 AC: 40 AN: 1093042 Hom.: 0 Cov.: 29 AF XY: 0.0000502 AC XY: 18 AN XY: 358560

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000663

Gnomad4 SAS exome AF: 0.000315

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000955

Gnomad4 OTH exome AF: 0.000131

GnomAD4 genome AF: 0.0000807 AC: 9 AN: 111542 Hom.: 0 Cov.: 23 AF XY: 0.0000889 AC XY: 3 AN XY: 33736

Gnomad4 AFR AF: 0.0000978

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000282

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000753

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000125

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000123 AC: 15

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2021

The c.422C>T (p.A141V) alteration is located in exon 6 (coding exon 5) of the MTM1 gene. This alteration results from a C to T substitution at nucleotide position 422, causing the alanine (A) at amino acid position 141 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 10, 2015

- -

Severe X-linked myotubular myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2022

MTM1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.69
Sift	Benign	0.053	T
Sift4G	Benign	0.16	T
Polyphen		1.0	D
Vest4		0.31
MVP		0.84
MPC		1.4
ClinPred		0.23	T
GERP RS		5.8
Varity_R		0.54
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs140642341; hg19: chrX-149787590;