16-2497026-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_001199107.2(TBC1D24):c.878G>A(p.Arg293His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,613,638 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001199107.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TBC1D24 | ENST00000646147.1 | c.878G>A | p.Arg293His | missense_variant | Exon 2 of 8 | NM_001199107.2 | ENSP00000494678.1 | |||
ENSG00000260272 | ENST00000564543.1 | c.878G>A | p.Arg293His | missense_variant | Exon 1 of 3 | 2 | ENSP00000455547.1 |
Frequencies
GnomAD3 genomes AF: 0.000223 AC: 34AN: 152232Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000193 AC: 48AN: 248774Hom.: 0 AF XY: 0.000193 AC XY: 26AN XY: 135058
GnomAD4 exome AF: 0.000334 AC: 488AN: 1461288Hom.: 0 Cov.: 31 AF XY: 0.000333 AC XY: 242AN XY: 726966
GnomAD4 genome AF: 0.000223 AC: 34AN: 152350Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17AN XY: 74508
ClinVar
Submissions by phenotype
not provided Uncertain:2
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24387994) -
TBC1D24: PM2, PM5 -
not specified Uncertain:1
The p.Arg293His variant in TBC1D24 has not been previously reported in individuals with hearing loss or DOORS syndrome, but has been identified in 0.034% (43/128356) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 207519). A different missense variant at the same position (p.Arg293Pro) has been reported to segregate with hearing loss in a Pakistani family (Rehman 2014). Computational prediction tools and conservation analysis suggest that the p.Arg293His variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM5_Supporting, PM2_Supporting, PP3. -
DOORS syndrome;C0917800:Familial infantile myoclonic epilepsy;C1842531:Rolandic epilepsy-paroxysmal exercise-induced dystonia-writer's cramp syndrome;C2829265:Autosomal recessive nonsyndromic hearing loss 86;C3809173:Developmental and epileptic encephalopathy, 16;C3892048:Autosomal dominant nonsyndromic hearing loss 65 Uncertain:1
- -
Inborn genetic diseases Uncertain:1
The p.R293H variant (also known as c.878G>A), located in coding exon 1 of the TBC1D24 gene, results from a G to A substitution at nucleotide position 878. The arginine at codon 293 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Developmental and epileptic encephalopathy, 1;C3892048:Autosomal dominant nonsyndromic hearing loss 65;CN236805:Caused by mutation in the TBC1 domain family, member 24 Uncertain:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 293 of the TBC1D24 protein (p.Arg293His). This variant is present in population databases (rs199700840, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with TBC1D24-related conditions. ClinVar contains an entry for this variant (Variation ID: 207519). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TBC1D24 protein function. 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at