chr16-2496789-G-A
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS1
The NM_001199107.2(TBC1D24):c.641G>A(p.Arg214His) variant causes a missense change. The variant allele was found at a frequency of 0.000958 in 1,613,990 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R214C) has been classified as Uncertain significance.
Frequency
Consequence
NM_001199107.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TBC1D24 | NM_001199107.2 | c.641G>A | p.Arg214His | missense_variant | 2/8 | ENST00000646147.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TBC1D24 | ENST00000646147.1 | c.641G>A | p.Arg214His | missense_variant | 2/8 | NM_001199107.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000795 AC: 121AN: 152232Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000972 AC: 242AN: 249014Hom.: 1 AF XY: 0.00114 AC XY: 154AN XY: 135264
GnomAD4 exome AF: 0.000976 AC: 1426AN: 1461640Hom.: 4 Cov.: 31 AF XY: 0.00100 AC XY: 730AN XY: 727140
GnomAD4 genome ? AF: 0.000788 AC: 120AN: 152350Hom.: 1 Cov.: 33 AF XY: 0.000819 AC XY: 61AN XY: 74502
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:3
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | TBC1D24: BP4, BS1 - |
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 14, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 15, 2023 | Identified with a second TBC1D24 variant on the opposite allele (in trans) in siblings with nonsyndromic hearing loss in published literature (Bakhchane et al., 2015); authors propose that the p.(R214H) variant may be hypomorphic, resulting in a milder phenotype; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27259978, 22277662, 24848745, 29741288, 32987832, 28428906, 34426522, 32860223, 29358611, 28301460, 27281533, 34440452, 35580552, 26371875, 36374051, 33986365) - |
not specified Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 01, 2019 | The p.Arg214His variant in TBC1D24 is classified as likely benign due to its high allele frequency. Although it has been reported in trans with a likely pathogenic variant in two Morroccan probands with hearing loss (2/272 alleles), it was also identified at a similar frequency in a race matched control population (1%, 4/400 chromosomes; Bakhchane 2015). Furthermore, this variant has been reported in several populations by gnomAD with a total allele frequency of 0.1% (271/280420) and an allele frequency of 0.19% (58/30602) of South Asian chromosomes including 1 homozygote. ACMG/AMP criteria: BS1. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 11, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Sep 24, 2015 | - - |
Autosomal recessive nonsyndromic hearing loss 86 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | May 31, 2018 | This recessive variant was identified in two brothers diagnosed with profound bilateral hearing loss. Both patients harbour also a second variant (see below) in this gene in compound heterozygosity - |
Developmental and epileptic encephalopathy, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Mar 05, 2018 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 22, 2018 | The p.R214H variant (also known as c.641G>A), located in coding exon 1 of the TBC1D24 gene, results from a G to A substitution at nucleotide position 641. The arginine at codon 214 is replaced by histidine, an amino acid with highly similar properties. This variant was identified with another TBC1D24 variant in three families with non-syndromic hearing loss; the variant was suggested to act as a hypomorph (Bakhchane A et al. PLoS ONE, 2015 Sep;10:e0138072; Rehman AU et al. Oral Dis, 2017 Jul;23:551-558). This variant was also detected in a patient with neonatal seizures and pervasive developmental disorder; however, the patient also had a de novo KCNQ2 mutation (Della Mina E et al. Eur. J. Hum. Genet., 2015 Mar;23:354-62). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. - |
Familial infantile myoclonic epilepsy Benign:1
Benign, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
Developmental and epileptic encephalopathy, 1;C3892048:Autosomal dominant nonsyndromic hearing loss 65;CN236805:Caused by mutation in the TBC1 domain family, member 24 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at