X-150614696-T-C

Variant names:

• chrX-150614696-T-C
• rs147644722
• NM_000252.3:c.339T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7 BA1 BP4

This summary comes from the ClinGen Evidence Repository: The variant NM_000252.3:c.339T>C in MTM1 is a synonymous (silent) variant (p.Cys113=). The highest population filtering allele frequency in gnomAD v4.1.0 is 0.003242 (198/54107 alleles, 58 hemizygotes) in African/African American population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.000016) for BA1, and therefore meets this criterion (BA1). In addition, SpliceAI does not predict impact to splicing, and the variant occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). In summary, this variant meets the criteria to be classified as benign for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4, BP7. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10539080/MONDO:0018947/149

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., 36 hem., cov: 22)
  • Exomes 𝑓: 0.00014 (0 hom. 32 hem.)
• Consequence: MTM1 NM_000252.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: 2.27
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	NM_000252.3	MANE Select	c.339T>C	p.Cys113Cys	synonymous	Exon 5 of 15	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.339T>C	p.Cys113Cys	synonymous	Exon 5 of 15	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.339T>C	p.Cys113Cys	synonymous	Exon 5 of 15	NP_001363835.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	ENST00000370396.7	TSL:1 MANE Select	c.339T>C	p.Cys113Cys	synonymous	Exon 5 of 15	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000689314.1		c.384T>C	p.Cys128Cys	synonymous	Exon 6 of 16	ENSP00000510607.1	A0A8I5KZ76
	MTM1	ENST00000866458.1		c.384T>C	p.Cys128Cys	synonymous	Exon 6 of 16	ENSP00000536517.1

Frequencies

GnomAD3 genomes AF: 0.000999 AC: 111 AN: 111075 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000575

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: 0.00134

GnomAD2 exomes AF: 0.000349 AC: 60 AN: 171830 AF XY: 0.000240

Gnomad AFR exome AF: 0.00381

Gnomad AMR exome AF: 0.000447

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000233

GnomAD4 exome AF: 0.000138 AC: 131 AN: 947186 Hom.: 0 Cov.: 19 AF XY: 0.000123 AC XY: 32 AN XY: 259486

African (AFR) AF: 0.00403 AC: 95 AN: 23558

American (AMR) AF: 0.000547 AC: 19 AN: 34757

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18313

East Asian (EAS) AF: 0.00 AC: 0 AN: 29327

South Asian (SAS) AF: 0.00 AC: 0 AN: 50097

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40089

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3793

European-Non Finnish (NFE) AF: 0.00000708 AC: 5 AN: 706023

Other (OTH) AF: 0.000291 AC: 12 AN: 41229

GnomAD4 genome AF: 0.000999 AC: 111 AN: 111129 Hom.: 0 Cov.: 22 AF XY: 0.00108 AC XY: 36 AN XY: 33349

African (AFR) AF: 0.00337 AC: 103 AN: 30549

American (AMR) AF: 0.000575 AC: 6 AN: 10440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2638

East Asian (EAS) AF: 0.00 AC: 0 AN: 3561

South Asian (SAS) AF: 0.00 AC: 0 AN: 2624

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5949

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52958

Other (OTH) AF: 0.00132 AC: 2 AN: 1510

Alfa AF: 0.000996 Hom.: 4

Bravo AF: 0.00133

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Centronuclear myopathy (1)
-	-	1	MTM1-related disorder (1)
-	-	1	not specified (1)
-	-	1	Severe X-linked myotubular myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.68
PhyloP100		2.3
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs147644722; hg19: chrX-149783169;