rs199700840
Positions:
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
Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00033 ( 0 hom. )
Consequence
TBC1D24
NM_001199107.2 missense
NM_001199107.2 missense
Scores
7
6
6
Clinical Significance
Conservation
PhyloP100: 9.93
Genes affected
TBC1D24 (HGNC:29203): (TBC1 domain family member 24) This gene encodes a protein with a conserved domain, referred to as the TBC domain, characteristic of proteins which interact with GTPases. TBC domain proteins may serve as GTPase-activating proteins for a particular group of GTPases, the Rab (Ras-related proteins in brain) small GTPases which are involved in the regulation of membrane trafficking. Mutations in this gene are associated with familial infantile myoclonic epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TBC1D24 | NM_001199107.2 | c.878G>A | p.Arg293His | missense_variant | 2/8 | ENST00000646147.1 | NP_001186036.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TBC1D24 | ENST00000646147.1 | c.878G>A | p.Arg293His | missense_variant | 2/8 | NM_001199107.2 | ENSP00000494678 | A1 |
Frequencies
GnomAD3 genomes AF: 0.000223 AC: 34AN: 152232Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000193 AC: 48AN: 248774Hom.: 0 AF XY: 0.000193 AC XY: 26AN XY: 135058
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GnomAD4 exome AF: 0.000334 AC: 488AN: 1461288Hom.: 0 Cov.: 31 AF XY: 0.000333 AC XY: 242AN XY: 726966
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GnomAD4 genome AF: 0.000223 AC: 34AN: 152350Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17AN XY: 74508
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 04, 2024 | 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) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2022 | TBC1D24: PM2, PM5 - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 13, 2019 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 03, 2022 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 06, 2019 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 30, 2023 | 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TBC1D24 protein function with a positive predictive value of 80%. 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
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
.;T;T;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;.;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M;.;.;M;.
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
T
PROVEAN
Uncertain
D;.;D;.;.;.;D
REVEL
Uncertain
Sift
Uncertain
D;.;D;.;.;.;D
Sift4G
Benign
T;.;T;.;.;T;D
Polyphen
D;D;D;.;.;D;.
Vest4
MVP
MPC
1.2, 1.6
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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