rs267607103
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM5BP4_Moderate
The NM_001199107.2(TBC1D24):c.439G>A(p.Asp147Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000659 in 1,609,514 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D147H) has been classified as Pathogenic.
Frequency
Consequence
NM_001199107.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TBC1D24 | NM_001199107.2 | c.439G>A | p.Asp147Asn | missense_variant | 2/8 | ENST00000646147.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TBC1D24 | ENST00000646147.1 | c.439G>A | p.Asp147Asn | missense_variant | 2/8 | NM_001199107.2 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152202Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000131 AC: 32AN: 244966Hom.: 0 AF XY: 0.000180 AC XY: 24AN XY: 133674
GnomAD4 exome AF: 0.0000624 AC: 91AN: 1457194Hom.: 0 Cov.: 31 AF XY: 0.0000786 AC XY: 57AN XY: 725174
GnomAD4 genome AF: 0.0000985 AC: 15AN: 152320Hom.: 1 Cov.: 33 AF XY: 0.0000671 AC XY: 5AN XY: 74472
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | Feb 09, 2022 | PM5_supporting - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 07, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
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 | Sep 09, 2021 | - - |
Familial infantile myoclonic epilepsy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 12, 2016 | The p.Asp147Asn variant in TBC1D24 has not been previously reported in individua ls with hearing loss. This variant has been identified in 0.1% (12/8488) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadi nstitute.org; dbSNP rs267607103). Although this variant has been seen in the gen eral population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses suggest that the p.Asp 147Asn variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of th e p.Asp147Asn variant is uncertain. - |
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 | Invitae | Dec 07, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 147 of the TBC1D24 protein (p.Asp147Asn). This variant is present in population databases (rs267607103, gnomAD 0.1%). 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: 229287). 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 not expected to disrupt TBC1D24 protein function with a negative predictive value of 80%. This variant disrupts the p.Asp147 amino acid residue in TBC1D24. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20727515). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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