chrX-101348591-AC-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The ENST00000372902.4(TIMM8A):c.73del(p.Val25Ter) variant causes a frameshift 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: 22)
Consequence
TIMM8A
ENST00000372902.4 frameshift
ENST00000372902.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.15
Genes affected
TIMM8A (HGNC:11817): (translocase of inner mitochondrial membrane 8A) This translocase is involved in the import and insertion of hydrophobic membrane proteins from the cytoplasm into the mitochondrial inner membrane. The gene is mutated in Mohr-Tranebjaerg syndrome/Deafness Dystonia Syndrome (MTS/DDS) and it is postulated that MTS/DDS is a mitochondrial disease caused by a defective mitochondrial protein import system. Defects in this gene also cause Jensen syndrome; an X-linked disease with opticoacoustic nerve atrophy and muscle weakness. This protein, along with TIMM13, forms a 70 kDa heterohexamer. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-101348591-AC-A is Pathogenic according to our data. Variant chrX-101348591-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 11322.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-101348591-AC-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TIMM8A | NM_004085.4 | c.73del | p.Val25Ter | frameshift_variant | 1/2 | ENST00000372902.4 | NP_004076.1 | |
TIMM8A | NM_001145951.2 | c.73del | p.Val25Ter | frameshift_variant | 1/2 | NP_001139423.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TIMM8A | ENST00000372902.4 | c.73del | p.Val25Ter | frameshift_variant | 1/2 | 1 | NM_004085.4 | ENSP00000361993 | P1 | |
TIMM8A | ENST00000644112.2 | c.73del | p.Val25Ter | frameshift_variant | 1/2 | ENSP00000494385 | ||||
TIMM8A | ENST00000645279.1 | c.73del | p.Val25Ter | frameshift_variant, NMD_transcript_variant | 1/3 | ENSP00000494239 | ||||
TIMM8A | ENST00000647480.1 | upstream_gene_variant |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD3 genomes
Cov.:
22
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 22
GnomAD4 genome
Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 12, 2023 | ClinVar contains an entry for this variant (Variation ID: 11322). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is also known as 108delG. This premature translational stop signal has been observed in individual(s) with Mohr-Tranebjaerg syndrome (PMID: 11601506). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val25*) in the TIMM8A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TIMM8A are known to be pathogenic (PMID: 11956200, 21984432, 22736418). - |
Deafness dystonia syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2001 | - - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at