rs587783848

Positions:

• chrX-150641416-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000252.3(MTM1):​c.676C>A​(p.Pro226Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,945 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: MTM1 NM_000252.3 missense, splice_region
• Scores: Splicing: ADA: 0.8521
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.46

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-150641416-C-A is Pathogenic according to our data. Variant chrX-150641416-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 158995.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150641416-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTM1	NM_000252.3	c.676C>A	p.Pro226Thr	missense_variant, splice_region_variant	8/15	ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7	c.676C>A	p.Pro226Thr	missense_variant, splice_region_variant	8/15	1	NM_000252.3	ENSP00000359423	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096945 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 362389

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Oct 15, 2009	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.80
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.95		Gain of MoRF binding (P = 0.0495);
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.85
dbscSNV1_RF	Benign	0.72
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

LitVar

Other links and lift over

dbSNP: rs587783848; hg19: chrX-149809889;