dbSNP rs373045797: MTM1:c.232-7A>G (chrX-150614582-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_000252.3(MTM1):c.232-7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000183 in 1,091,359 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000015 ( 0 hom. 3 hem. )

Consequence

MTM1
NM_000252.3 splice_region, intron

Scores

Splicing: ADA: 0.004730

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.924

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant X-150614582-A-G is Benign according to our data. Variant chrX-150614582-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 461697.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTM1	NM_000252.3 link	c.232-7A>G		splice_region_variant, intron_variant	Intron 4 of 14	ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7 link	c.232-7A>G		splice_region_variant, intron_variant	Intron 4 of 14	1	NM_000252.3	ENSP00000359423.3

Frequencies

GnomAD3 genomes

AF:

0.0000447

AC:

AN:

111743

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000950

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000175

AC:

AN:

171003

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000820

Gnomad AMR exome

AF:

0.0000373

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000135

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000153

AC:

AN:

979616

Hom.:

Cov.:

AF XY:

0.0000104

AC XY:

AN XY:

287156

show subpopulations

African (AFR)

AF:

0.0000829

AC:

AN:

24124

American (AMR)

AF:

0.0000574

AC:

AN:

34813

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18521

East Asian (EAS)

AF:

0.00

AC:

AN:

29522

South Asian (SAS)

AF:

0.00

AC:

AN:

50943

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40098

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3887

European-Non Finnish (NFE)

AF:

0.0000150

AC:

AN:

735497

Other (OTH)

AF:

0.00

AC:

AN:

42211

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.546

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:

0.0000447

AC:

AN:

111743

Hom.:

Cov.:

AF XY:

0.0000590

AC XY:

AN XY:

33911

show subpopulations

African (AFR)

AF:

0.000130

AC:

AN:

30660

American (AMR)

AF:

0.0000950

AC:

AN:

10523

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3574

South Asian (SAS)

AF:

0.00

AC:

AN:

2676

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6021

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53213

Other (OTH)

AF:

0.00

AC:

AN:

1510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.0000453

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Severe X-linked myotubular myopathy

Benign:1

Feb 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

9.9

(source)

DANN

Benign

0.80

PhyloP100

0.92

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0047

dbscSNV1_RF

Benign

0.040

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over