rs184956219

chrX-150596484-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000252.3(MTM1):c.64-14T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00537 in 1,194,712 control chromosomes in the GnomAD database, including 18 homozygotes. There are 2,126 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (0 hom., 103 hem., cov: 23)
  • Exomes 𝑓: 0.0056 (18 hom. 2023 hem.)
• Consequence: MTM1 NM_000252.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.123

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-150596484-T-C is Benign according to our data. Variant chrX-150596484-T-C is described in ClinVar as [Benign]. Clinvar id is 158992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596484-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00343 (384/112039) while in subpopulation NFE AF= 0.00539 (287/53241). AF 95% confidence interval is 0.00488. There are 0 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 103 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTM1	NM_000252.3	c.64-14T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000370396.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTM1	ENST00000370396.7	c.64-14T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000252.3	P1

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 385 AN: 111993 Hom.: 0 Cov.: 23 AF XY: 0.00302 AC XY: 103 AN XY: 34139

Gnomad AFR AF: 0.000975

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00565

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.000657

Gnomad MID AF: 0.0168

Gnomad NFE AF: 0.00539

Gnomad OTH AF: 0.00731

GnomAD3 exomes AF: 0.00466 AC: 851 AN: 182505 Hom.: 1 AF XY: 0.00542 AC XY: 364 AN XY: 67097

Gnomad AFR exome AF: 0.00107

Gnomad AMR exome AF: 0.00183

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0103

Gnomad FIN exome AF: 0.00133

Gnomad NFE exome AF: 0.00636

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.00557 AC: 6033 AN: 1082673 Hom.: 18 Cov.: 27 AF XY: 0.00577 AC XY: 2023 AN XY: 350577

Gnomad4 AFR exome AF: 0.000881

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.00638

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0106

Gnomad4 FIN exome AF: 0.00141

Gnomad4 NFE exome AF: 0.00594

Gnomad4 OTH exome AF: 0.00554

GnomAD4 genome AF: 0.00343 AC: 384 AN: 112039 Hom.: 0 Cov.: 23 AF XY: 0.00301 AC XY: 103 AN XY: 34195

Gnomad4 AFR AF: 0.000973

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00565

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00520

Gnomad4 FIN AF: 0.000657

Gnomad4 NFE AF: 0.00539

Gnomad4 OTH AF: 0.00722

Alfa AF: 0.00422 Hom.: 33

Bravo AF: 0.00317

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Severe X-linked myotubular myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	2.6
Dann	Benign	0.57

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: rs184956219; hg19: chrX-149764948;