rs140642341

Positions:

chrX-150619117-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 7.48

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Likely_benign=3, Uncertain_significance=1, Benign=1}.

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 linkuse as main transcript	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 linkuse as main transcript	c.422C>T	p.Ala141Val	missense_variant	6/15	1	NM_000252.3	P1	Q13496-1

Frequencies

GnomAD3 genomes

AF:

0.0000807

AC:

AN:

111487

Hom.:

Cov.:

AF XY:

0.0000891

AC XY:

AN XY:

33671

show subpopulations

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:

AN:

183221

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

67753

show subpopulations

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:

AN:

1093042

Hom.:

Cov.:

AF XY:

0.0000502

AC XY:

AN XY:

358560

show subpopulations

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:

AN:

111542

Hom.:

Cov.:

AF XY:

0.0000889

AC XY:

AN XY:

33736

show subpopulations

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:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000123

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	MTM1: BS2 -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.90

MetaRNN

Uncertain

0.50

MetaSVM

Uncertain

0.61

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.69

Sift

Benign

0.053

Sift4G

Benign

0.16

Polyphen

1.0

Vest4

0.31

MVP

0.84

MPC

1.4

ClinPred

0.23

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over