rs367912069

Variant names:

• chrX-150641322-C-T
• rs367912069
• NM_000252.3:c.582C>T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The variant NM_000252.3(MTM1):c.582C>T is a synonymous (silent) variant (p.Leu194=). The filtering allele frequency in gnomAD v4.1.0 is 0.002821 (112/33731 alleles, 2 homozygote, 36 hemizygotes) for the East Asian population, which is higher than the ClinGen congenital myopathy MTM1 threshold (≥0.000016) for BA1, and therefore meets this criterion (BA1). In addition, SpliceAI predicted no impact on splicing, meeting BP4/BP7 criteria. In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: BA1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10539132/MONDO:0018947/149

• Frequency:
  • Genomes: 𝑓 0.00031 (2 hom., 7 hem., cov: 22)
  • Exomes 𝑓: 0.00013 (2 hom. 36 hem.)
• Consequence: MTM1 NM_000252.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: -0.303
• 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

Specifications for MTM1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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.582C>T	p.Leu194Leu	synonymous	Exon 8 of 15	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.582C>T	p.Leu194Leu	synonymous	Exon 8 of 15	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.582C>T	p.Leu194Leu	synonymous	Exon 8 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.582C>T	p.Leu194Leu	synonymous	Exon 8 of 15	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000688403.1		c.-163C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 10	ENSP00000508944.1	A0A8I5KQR6
	MTM1	ENST00000690282.1		c.-163C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 10	ENSP00000509809.1	A0A8I5KQR6

Frequencies

GnomAD3 genomes AF: 0.000314 AC: 35 AN: 111621 Hom.: 2 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000569

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00788

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000663

GnomAD2 exomes AF: 0.000323 AC: 59 AN: 182841 AF XY: 0.000341

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00426

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000132 AC: 145 AN: 1097561 Hom.: 2 Cov.: 30 AF XY: 0.0000992 AC XY: 36 AN XY: 362971

African (AFR) AF: 0.00 AC: 0 AN: 26380

American (AMR) AF: 0.00 AC: 0 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.00278 AC: 84 AN: 30190

South Asian (SAS) AF: 0.00 AC: 0 AN: 54131

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841563

Other (OTH) AF: 0.00128 AC: 59 AN: 46067

GnomAD4 genome AF: 0.000313 AC: 35 AN: 111674 Hom.: 2 Cov.: 22 AF XY: 0.000207 AC XY: 7 AN XY: 33858

African (AFR) AF: 0.00 AC: 0 AN: 30729

American (AMR) AF: 0.000569 AC: 6 AN: 10553

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00791 AC: 28 AN: 3541

South Asian (SAS) AF: 0.00 AC: 0 AN: 2597

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6075

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53111

Other (OTH) AF: 0.000655 AC: 1 AN: 1527

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000280

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	5.9
DANN	Benign	0.74
PhyloP100		-0.30
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs367912069; hg19: chrX-149809795;