rs1322584849
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000252.3(MTM1):c.867+4A>T variant causes a splice donor 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. Variant has been reported in ClinVar as Uncertain significance (★).
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_donor_region, intron
NM_000252.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9109
2
Clinical Significance
Conservation
PhyloP100: 4.01
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.33).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MTM1 | NM_000252.3 | c.867+4A>T | splice_donor_region_variant, intron_variant | ENST00000370396.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MTM1 | ENST00000370396.7 | c.867+4A>T | splice_donor_region_variant, intron_variant | 1 | NM_000252.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000891 AC: 1AN: 112286Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 34448
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GnomAD3 exomes AF: 0.00000548 AC: 1AN: 182589Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67361
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GnomAD4 exome AF: 0.00000458 AC: 5AN: 1090616Hom.: 0 Cov.: 29 AF XY: 0.00000281 AC XY: 1AN XY: 356256
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GnomAD4 genome ? AF: 0.00000891 AC: 1AN: 112286Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 34448
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Severe X-linked myotubular myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 07, 2017 | This sequence change falls in intron 9 of the MTM1 gene. It does not directly change the encoded amino acid sequence of the MTM1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MTM1-related disease. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -4
Find out detailed SpliceAI scores and Pangolin per-transcript scores at