Genetic Variant NM_000252.3:c.526C>A (chrX-150639024-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000252.3(MTM1):c.526C>A(p.Gln176Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q176Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

MTM1
NM_000252.3 missense, splice_region

Scores

Splicing: ADA: 0.5646

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.27

Publications

0 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: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, Orphanet

MTM1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_000252.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.875

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
MTM1	NM_000252.3	MANE Select	c.526C>A	p.Gln176Lys	missense splice_region	Exon 7 of 15	NP_000243.1
MTM1	NM_001376908.1		c.526C>A	p.Gln176Lys	missense splice_region	Exon 7 of 15	NP_001363837.1
MTM1	NM_001376906.1		c.526C>A	p.Gln176Lys	missense splice_region	Exon 7 of 15	NP_001363835.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MTM1	ENST00000370396.7	TSL:1 MANE Select	c.526C>A	p.Gln176Lys	missense splice_region	Exon 7 of 15	ENSP00000359423.3
MTM1	ENST00000689314.1		c.571C>A	p.Gln191Lys	missense splice_region	Exon 8 of 16	ENSP00000510607.1
MTM1	ENST00000685944.1		c.526C>A	p.Gln176Lys	missense splice_region	Exon 7 of 15	ENSP00000509266.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1070397

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

337993

African (AFR)

AF:

0.00

AC:

AN:

25852

American (AMR)

AF:

0.00

AC:

AN:

35174

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19197

East Asian (EAS)

AF:

0.00

AC:

AN:

30069

South Asian (SAS)

AF:

0.00

AC:

AN:

53492

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40513

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4075

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

816844

Other (OTH)

AF:

0.00

AC:

AN:

45181

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Severe X-linked myotubular myopathy

Uncertain:1

May 31, 2013

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.88

MetaSVM

Pathogenic

0.84

MutationAssessor

Pathogenic

3.6

PhyloP100

7.3

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.6

REVEL

Pathogenic

0.75

Sift

Benign

0.20

Sift4G

Benign

0.65

Polyphen

0.61

Vest4

0.85

MutPred

0.45

Gain of ubiquitination at Q176 (P = 0.0267)

MVP

0.98

MPC

1.1

ClinPred

0.97

GERP RS

5.3

Varity_R

0.96

gMVP

0.99

Mutation Taster

=33/67

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.56

dbscSNV1_RF

Benign

0.70

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

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over