rs140642341

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 was made for transcript

Our verdict: Benign. The variant received -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, Likely_benign=3, Benign=1}.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000366 (40/1093042) while in subpopulation MID AF = 0.000969 (4/4126). AF 95% confidence interval is 0.00033. There are 0 homozygotes in GnomAdExome4. There are 18 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position FAILED quality control check.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTM1	NM_000252.3 link	c.422C>T	p.Ala141Val	missense_variant	Exon 6 of 15	ENST00000370396.7	NP_000243.1	Q13496-1A0A024RC06

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7 link	c.422C>T	p.Ala141Val	missense_variant	Exon 6 of 15	1	NM_000252.3	ENSP00000359423.3		Q13496-1

Frequencies

GnomAD3 genomes

AF:

0.0000807

AC:

AN:

111487

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000819

AC:

AN:

183221

AF XY:

0.000118

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 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

AC:

AN:

26314

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

35203

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

19364

Gnomad4 EAS exome

AF:

0.0000663

AC:

AN:

30176

Gnomad4 SAS exome

AF:

0.000315

AC:

AN:

54044

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

40524

Gnomad4 NFE exome

AF:

0.00000955

AC:

AN:

837356

Gnomad4 Remaining exome

AF:

0.000131

AC:

AN:

45935

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

AC:

0.0000978027

AN:

0.0000978027

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.000282

AC:

0.000282326

AN:

0.000282326

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000753

AC:

0.0000752913

AN:

0.0000752913

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MTM1: BS2 -

Inborn genetic diseases

Uncertain:1

Oct 27, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Apr 10, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Severe X-linked myotubular myopathy

Benign:1

Jan 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

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

Mutation Taster

=81/19

polymorphism

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