16-2496789-G-A

Position:

chr16-2496789-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

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).

Frequency

Genomes: 𝑓 0.00079 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00098 ( 4 hom. )

Consequence

TBC1D24
NM_001199107.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6B:6

Conservation

PhyloP100: 3.99

Variant links:

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]

TBC1D24 links:

ENSG00000260272 (HGNC:):

ENSG00000260272 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a domain Rab-GAP TBC (size 215) in uniprot entity TBC24_HUMAN there are 17 pathogenic changes around while only 3 benign (85%) 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: {Likely_benign=4, Uncertain_significance=6, Benign=2, Likely_pathogenic=1}.

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.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D24	NM_001199107.2 linkuse as main transcript	c.641G>A	p.Arg214His	missense_variant	2/8	ENST00000646147.1	NP_001186036.1	Q9ULP9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D24	ENST00000646147.1 linkuse as main transcript	c.641G>A	p.Arg214His	missense_variant	2/8		NM_001199107.2	ENSP00000494678.1		Q9ULP9-1
ENSG00000260272	ENST00000564543.1 linkuse as main transcript	c.641G>A	p.Arg214His	missense_variant	1/3	2		ENSP00000455547.1		H3BQ06

Frequencies

GnomAD3 genomes

AF:

0.000795

AC:

121

AN:

152232

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00114

AC XY:

154

AN XY:

135264

show subpopulations

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.:

Cov.:

AF XY:

0.00100

AC XY:

730

AN XY:

727140

show subpopulations

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.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74502

show subpopulations

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.:

Bravo

AF:

0.000812

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000471

AC:

ESP6500EA

AF:

0.00141

AC:

ExAC

AF:

0.00102

AC:

123

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00256

EpiControl

AF:

0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:6Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 14, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	TBC1D24: BP4, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2024	Identified with a second TBC1D24 variant on the opposite allele (in trans) in siblings with nonsyndromic hearing loss in published literature; authors propose that the p.(R214H) variant may be hypomorphic, resulting in a milder phenotype (PMID: 26371875); In silico analysis indicates 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, 36515421, 36964972, 37811145) -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

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

Pathogenic:1Uncertain: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 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 11, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene (PMID: 27281533). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Only a single missense has been reported to cause autosomal dominant disease (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine (exon 2). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (269 heterozygotes, 1 homozygote). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (3 heterozygotes, 0 homozygotes). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif, (Rab-GTPase-TBC domain; PDB, NCBI). (N) 0705 - A comparable variant (p.Arg214Cys) has been previous reported as a VUS (ClinVar). (N) 0808 - Previous reports of pathogenicity are conflicting. This variant has been reported as a VUS, likely benign and likely pathogenic (ClinVar, LOVD). All reports of this variant being benign are in relation to epilepsy studies (PMID: 24848745, PMID: 29358611), however, this variant has been called a hypomorphic allele, and disease causing within deafness patients (PMID: 26371875, PMID: 28951997). (N) 0901 - Strong evidence for segregation with disease. This variant has been shown to segregate in two families with hearing loss (PMID: 26371875). (P) 1007 - No published functional evidence has been identified for this variant. (N) 1201 - Heterozygous variant detected in trans with a second (at least likely) pathogenic heterozygous variant in a recessive disease (IGV). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.052

.;T;T;.;.;.;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

.;.;D;D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.014

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M;M;.;.;M;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.63

N;.;N;.;.;.;N

REVEL

Benign

0.19

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over