rs200324356

chr16-2496789-G-Achr16-2496789-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS1

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:
  • Genomes: 𝑓 0.00079 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00098 (4 hom.)
• Consequence: TBC1D24 NM_001199107.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:6
• Conservation: PhyloP100: 3.99

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM1: In a domain Rab-GAP TBC (size 215) in uniprot entity TBC24_HUMAN there are 39 pathogenic changes around while only 10 benign (80%) in NM_001199107.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.013885826).
• BP6: Variant 16-2496789-G-A is Benign according to our data. Variant chr16-2496789-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130540.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=4, Benign=2}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000788 (120/152350) while in subpopulation SAS AF= 0.0029 (14/4828). AF 95% confidence interval is 0.00175. There are 1 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

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: 121 AN: 152232 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000972 AC: 242 AN: 249014 Hom.: 1 AF XY: 0.00114 AC XY: 154 AN XY: 135264

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000956

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00190

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.000976 AC: 1426 AN: 1461640 Hom.: 4 Cov.: 31 AF XY: 0.00100 AC XY: 730 AN XY: 727140

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00198

Gnomad4 FIN exome AF: 0.0000564

Gnomad4 NFE exome AF: 0.000986

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.000788 AC: 120 AN: 152350 Hom.: 1 Cov.: 33 AF XY: 0.000819 AC XY: 61 AN XY: 74502

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00121

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.000812

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000471 AC: 2

ESP6500EA AF: 0.00141 AC: 12

ExAC AF: 0.00102 AC: 123

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign: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:2 Benign: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	25
Dann	Pathogenic	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.014	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M;M;.;.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.63	N;.;N;.;.;.;N
Sift	Benign	0.067	T;.;T;.;.;.;T
Sift4G	Benign	0.23	T;.;T;.;.;T;T
Polyphen		1.0	D;D;D;.;.;D;.
Vest4		0.64
MVP		0.77
MPC		1.1, 1.5
ClinPred		0.046	T
GERP RS		5.4
Varity_R		0.18
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200324356; hg19: chr16-2546790; COSMIC: COSV53547158; COSMIC: COSV53547158;