rs1322584849

Variant names:

• chrX-150645875-A-T
• rs1322584849
• NM_000252.3:c.867+4A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000252.3(MTM1):​c.867+4A>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000499 in 1,202,902 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). The gene MTM1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: MTM1 NM_000252.3 splice_region, intron
• Scores: Splicing: ADA: 0.9109
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.01
• 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: ClinGen, G2P, Orphanet, Genomics England PanelApp, Myriad Women's Health, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).

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.867+4A>T		splice_region intron	N/A	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.867+4A>T		splice_region intron	N/A	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.867+4A>T		splice_region intron	N/A	NP_001363835.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	ENST00000370396.7	TSL:1 MANE Select	c.867+4A>T		splice_region intron	N/A	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000689314.1		c.912+4A>T		splice_region intron	N/A	ENSP00000510607.1	A0A8I5KZ76
	MTM1	ENST00000866458.1		c.912+4A>T		splice_region intron	N/A	ENSP00000536517.1

Frequencies

GnomAD3 genomes AF: 0.00000891 AC: 1 AN: 112286 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.00000548 AC: 1 AN: 182589 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000458 AC: 5 AN: 1090616 Hom.: 0 Cov.: 29 AF XY: 0.00000281 AC XY: 1 AN XY: 356256

African (AFR) AF: 0.00 AC: 0 AN: 26238

American (AMR) AF: 0.00 AC: 0 AN: 35149

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19340

East Asian (EAS) AF: 0.00 AC: 0 AN: 30149

South Asian (SAS) AF: 0.00 AC: 0 AN: 53986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40527

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4113

European-Non Finnish (NFE) AF: 0.00000599 AC: 5 AN: 835268

Other (OTH) AF: 0.00 AC: 0 AN: 45846

GnomAD4 genome AF: 0.00000891 AC: 1 AN: 112286 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34448

African (AFR) AF: 0.0000324 AC: 1 AN: 30893

American (AMR) AF: 0.00 AC: 0 AN: 10581

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3604

South Asian (SAS) AF: 0.00 AC: 0 AN: 2731

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6111

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53285

Other (OTH) AF: 0.00 AC: 0 AN: 1511

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Severe X-linked myotubular myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Benign	0.93
PhyloP100		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.91
dbscSNV1_RF	Benign	0.50
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.28		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1322584849;

hg19: chrX-149814348;