rs587783806

chrX-150671484-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000252.3(MTM1):c.1701C>T(p.Tyr567=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000437 in 1,208,934 control chromosomes in the GnomAD database, including 1 homozygotes. There are 276 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., 5 hem., cov: 22)
  • Exomes 𝑓: 0.00046 (1 hom. 271 hem.)
• Consequence: MTM1 NM_000252.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.0740

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant X-150671484-C-T is Benign according to our data. Variant chrX-150671484-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158951.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}. Variant chrX-150671484-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.074 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000189 (21/110831) while in subpopulation SAS AF= 0.00424 (11/2592). AF 95% confidence interval is 0.00238. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTM1	NM_000252.3	c.1701C>T	p.Tyr567=	synonymous_variant	15/15	ENST00000370396.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTM1	ENST00000370396.7	c.1701C>T	p.Tyr567=	synonymous_variant	15/15	1	NM_000252.3	P1

Frequencies

GnomAD3 genomes AF: 0.000190 AC: 21 AN: 110774 Hom.: 0 Cov.: 22 AF XY: 0.000152 AC XY: 5 AN XY: 32948

Gnomad AFR AF: 0.0000329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000966

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000282

Gnomad SAS AF: 0.00424

Gnomad FIN AF: 0.000514

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000755

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000873 AC: 160 AN: 183272 Hom.: 0 AF XY: 0.00133 AC XY: 90 AN XY: 67738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.00587

Gnomad FIN exome AF: 0.000376

Gnomad NFE exome AF: 0.000416

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000462 AC: 507 AN: 1098103 Hom.: 1 Cov.: 31 AF XY: 0.000746 AC XY: 271 AN XY: 363465

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.00624

Gnomad4 FIN exome AF: 0.000321

Gnomad4 NFE exome AF: 0.000139

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000189 AC: 21 AN: 110831 Hom.: 0 Cov.: 22 AF XY: 0.000151 AC XY: 5 AN XY: 33015

Gnomad4 AFR AF: 0.0000328

Gnomad4 AMR AF: 0.0000964

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000283

Gnomad4 SAS AF: 0.00424

Gnomad4 FIN AF: 0.000514

Gnomad4 NFE AF: 0.0000755

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000521 Hom.: 3

Bravo AF: 0.0000982

EpiCase AF: 0.000491

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Severe X-linked myotubular myopathy Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	2.5
Dann	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs587783806; hg19: chrX-149839957; COSMIC: COSV60337963;