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

Publications

2 publications found

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 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

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 VariationId is 211534.

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 passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 3 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTM1	NM_000252.3	MANE Select	c.422C>T	p.Ala141Val	missense	Exon 6 of 15	NP_000243.1	Q13496-1
MTM1	NM_001376908.1		c.422C>T	p.Ala141Val	missense	Exon 6 of 15	NP_001363837.1	Q13496-1
MTM1	NM_001376906.1		c.422C>T	p.Ala141Val	missense	Exon 6 of 15	NP_001363835.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTM1	ENST00000370396.7	TSL:1 MANE Select	c.422C>T	p.Ala141Val	missense	Exon 6 of 15	ENSP00000359423.3	Q13496-1
MTM1	ENST00000689314.1		c.467C>T	p.Ala156Val	missense	Exon 7 of 16	ENSP00000510607.1	A0A8I5KZ76
MTM1	ENST00000866458.1		c.467C>T	p.Ala156Val	missense	Exon 7 of 16	ENSP00000536517.1

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

African (AFR)

AF:

0.000114

AC:

AN:

26314

American (AMR)

AF:

0.00

AC:

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19364

East Asian (EAS)

AF:

0.0000663

AC:

AN:

30176

South Asian (SAS)

AF:

0.000315

AC:

AN:

54044

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40524

Middle Eastern (MID)

AF:

0.000969

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.00000955

AC:

AN:

837356

Other (OTH)

AF:

0.000131

AC:

AN:

45935

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

African (AFR)

AF:

0.0000978

AC:

AN:

30674

American (AMR)

AF:

0.00

AC:

AN:

10521

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2637

East Asian (EAS)

AF:

0.000282

AC:

AN:

3542

South Asian (SAS)

AF:

0.00

AC:

AN:

2639

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6000

Middle Eastern (MID)

AF:

0.00463

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000753

AC:

AN:

53127

Other (OTH)

AF:

0.00

AC:

AN:

1501

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

not specified (1)

Severe X-linked myotubular myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

(source)

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

PhyloP100

7.5

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

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over