chrX-150614703-A-G

Variant names:

• chrX-150614703-A-G
• rs587783820
• NM_000252.3:c.342+4A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The ENST00000370396.7(MTM1):​c.342+4A>G variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MTM1 ENST00000370396.7 splice_region, intron
• Scores: Splicing: ADA: 0.9953
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.38
• 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: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-150614703-A-G is Pathogenic according to our data. Variant chrX-150614703-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 158966.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000370396.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	NM_000252.3	MANE Select	c.342+4A>G		splice_region intron	N/A	NP_000243.1
	MTM1	NM_001376908.1		c.342+4A>G		splice_region intron	N/A	NP_001363837.1
	MTM1	NM_001376906.1		c.342+4A>G		splice_region intron	N/A	NP_001363835.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	ENST00000370396.7	TSL:1 MANE Select	c.342+4A>G		splice_region intron	N/A	ENSP00000359423.3
	MTM1	ENST00000689314.1		c.387+4A>G		splice_region intron	N/A	ENSP00000510607.1
	MTM1	ENST00000685944.1		c.342+4A>G		splice_region intron	N/A	ENSP00000509266.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 885637 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 232279

African (AFR) AF: 0.00 AC: 0 AN: 22278

American (AMR) AF: 0.00 AC: 0 AN: 34578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17920

East Asian (EAS) AF: 0.00 AC: 0 AN: 29021

South Asian (SAS) AF: 0.00 AC: 0 AN: 48728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39955

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3667

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 650303

Other (OTH) AF: 0.00 AC: 0 AN: 39187

GnomAD4 genome Cov.: 22

Alfa AF: 0.000173 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

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	-0.24
CADD	Benign	17
DANN	Benign	0.96
PhyloP100		6.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.78		Position offset: -4

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

Other links and lift over

dbSNP: rs587783820; hg19: chrX-149783176;