chrX-150614586-C-A

Variant names:

• chrX-150614586-C-A
• rs587783814
• NM_000252.3:c.232-3C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_000252.3(MTM1):​c.232-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.9e-7 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MTM1 NM_000252.3 splice_region, intron
• Scores: Splicing: ADA: 0.9109
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.74
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-150614586-C-A is Pathogenic according to our data. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150614586-C-A is described in CliVar as Pathogenic. Clinvar id is 158960.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTM1	NM_000252.3	c.232-3C>A		splice_region_variant, intron_variant	Intron 4 of 14	ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7	c.232-3C>A		splice_region_variant, intron_variant	Intron 4 of 14	1	NM_000252.3	ENSP00000359423.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.92e-7 AC: 1 AN: 1007845 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 302171

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24664

American (AMR) AF: 0.00 AC: 0 AN: 34863

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18681

East Asian (EAS) AF: 0.00 AC: 0 AN: 29623

South Asian (SAS) AF: 0.00 AC: 0 AN: 51603

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40159

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3958

European-Non Finnish (NFE) AF: 0.00000131 AC: 1 AN: 761185

Other (OTH) AF: 0.00 AC: 0 AN: 43109

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Benign	0.77
PhyloP100		1.7
Mutation Taster		=14/86	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.91
dbscSNV1_RF	Benign	0.62
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.47		Position offset: 3

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

Other links and lift over

dbSNP: rs587783814; hg19: chrX-149783059;