chrX-101346657-TCTC-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM4_SupportingPP3_ModeratePP5
The NM_004085.4(TIMM8A):c.133_135del(p.Glu45del) variant causes a inframe deletion, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 23)
Consequence
TIMM8A
NM_004085.4 inframe_deletion, splice_region
NM_004085.4 inframe_deletion, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.79
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 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_004085.4. Strenght limited to Supporting due to length of the change: 1aa.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant X-101346657-TCTC-T is Pathogenic according to our data. Variant chrX-101346657-TCTC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1303795.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TIMM8A | NM_004085.4 | c.133_135del | p.Glu45del | inframe_deletion, splice_region_variant | 2/2 | ENST00000372902.4 | |
TIMM8A | NM_001145951.2 | c.*1727_*1729del | 3_prime_UTR_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TIMM8A | ENST00000372902.4 | c.133_135del | p.Glu45del | inframe_deletion, splice_region_variant | 2/2 | 1 | NM_004085.4 | P1 | |
TIMM8A | ENST00000644112.2 | c.*1727_*1729del | 3_prime_UTR_variant | 2/2 | |||||
TIMM8A | ENST00000647480.1 | n.650_652del | splice_region_variant, non_coding_transcript_exon_variant | 2/2 | |||||
TIMM8A | ENST00000645279.1 | c.*327_*329del | splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant | 3/3 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Auditory neuropathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | WangQJ Lab, Chinese People's Liberation Army General Hospital | Dec 22, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 17, 2019 | Not observed in large population cohorts (Lek et al., 2016); In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30634948) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 0
DS_AL_spliceai
Position offset: 3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at