X-150568596-CAGAGGGGGCGGAGCAGGGCCCGGCAGCCGAGCAGCCTGGCAACGGCGGTGGCGCCCGGAGCCCGAG-C

Position:

• chrX-150568596-CAGAGGGGGCGGAGCAGGGCCCGGCAGCCGAGCAGCCTGGCAACGGCGGTGGCGCCCGGAGCCCGAG-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The X-150568596-CAGAGGGGGCGGAGCAGGGCCCGGCAGCCGAGCAGCCTGGCAACGGCGGTGGCGCCCGGAGCCCGAG-C variant causes a splice region, 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 25)
• Consequence: MTM1 NM_000252.3 splice_region, 5_prime_UTR
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.26

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-150568596-CAGAGGGGGCGGAGCAGGGCCCGGCAGCCGAGCAGCCTGGCAACGGCGGTGGCGCCCGGAGCCCGAG-C is Pathogenic according to our data. Variant chrX-150568596-CAGAGGGGGCGGAGCAGGGCCCGGCAGCCGAGCAGCCTGGCAACGGCGGTGGCGCCCGGAGCCCGAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 2500781.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTM1	NM_000252.3			splice_region_variant, 5_prime_UTR_variant	1/15	ENST00000370396.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTM1	ENST00000370396.7			splice_region_variant, 5_prime_UTR_variant	1/15	1	NM_000252.3	P1

Frequencies

GnomAD3 genomes Cov.: 25

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

-

- Non-coding variant with known effect. This 5’UTR variant deletes the transcription start site (TSS) of the canonical transcript. Sequencing of blood derived RNA (in-house, non-accredited) indicates complete loss of transcription initiation from the affected TSS, while transcription is retained in the unaffected parents. There was no indication of significant transcription from an alternative TSS. - Variant is absent from gnomAD (both v2 and v3). - This variant has limited previous evidence of pathogenicity in unrelated individual(s). A deletion of MTM1 Exon 1 has been described in two brothers with myotubular myopathy (PMID 9931531, 12467749), however exact coordinates of the described deletion were not available. - Very strong and specific phenotype match for this individual. A muscle biopsie from the patient has confirmed the clinical diagnosis of myotubular myopathy. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-149737046;