rs376712059

chr16-2496605-G-Achr16-2496605-G-Cchr16-2496605-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP5

The NM_001199107.2(TBC1D24):c.457G>A(p.Glu153Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000515 in 1,610,414 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E153A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

TBC1D24
NM_001199107.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:1

Conservation

PhyloP100: 6.67

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 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

PP5

Variant 16-2496605-G-A is Pathogenic according to our data. Variant chr16-2496605-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 207499.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Likely_pathogenic=5, Uncertain_significance=1}. Variant chr16-2496605-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D24	NM_001199107.2 linkuse as main transcript	c.457G>A	p.Glu153Lys	missense_variant	2/8	ENST00000646147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D24	ENST00000646147.1 linkuse as main transcript	c.457G>A	p.Glu153Lys	missense_variant	2/8		NM_001199107.2	A1	Q9ULP9-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000691

AC:

AN:

245952

Hom.:

AF XY:

0.0000970

AC XY:

AN XY:

134050

show subpopulations

Gnomad AFR exome

AF:

0.0000653

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000153

Gnomad NFE exome

AF:

0.000107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000542

AC:

AN:

1458174

Hom.:

Cov.:

AF XY:

0.0000524

AC XY:

AN XY:

725614

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000141

Gnomad4 NFE exome

AF:

0.0000585

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000194

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000825

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 13, 2022	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with epileptic encephalopathy and appears to segregate with disease in at least one family with infantile myoclonic epilepsy. Computational tools predict that this variant is damaging. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 14, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 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 second 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: 24291220, 27259978, 25769375, 28428906, 32004315, 28292732, 27652284, 27281533, 31216405, 33619735, 34852372, Timpanaro2021[Review], 28726039, 33986365, 35350397, 26371875) -

DOORS syndrome;C0917800:Familial infantile myoclonic epilepsy;C2829265:Autosomal recessive nonsyndromic hearing loss 86;C3809173:Developmental and epileptic encephalopathy, 16;C3892048:Autosomal dominant nonsyndromic hearing loss 65

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 12, 2018

- -

DOORS syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Jun 07, 2019

- -

Developmental and epileptic encephalopathy, 16

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Nov 15, 2022

Criteria applied: PS1,PS4_MOD,PM2_SUP -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 13, 2017

The p.Glu153Lys variant in TBC1D24 has been indentified in 5 individuals with TB C1D24-associated features. One individual had nonsyndromic hearing loss and was compound heterozygote for this variant as well as a VUS variant, both of which s egregated in a sibling with hearing loss (Bakhchane 2015). This variant has now been identified by our laboratory in an individual with hearing loss in trans wi th a TBC1D24 variant of uncertain significance (LMM data). Another individual p resented with a seizure disorder who initially passed an early hearing screen bu t developed profound deafness reported by 5 years of age (Ngoh 2017). This indiv idual was compound heterozygous for the p.Glu153Lys variant and a pathogenic var iant in TBC1D24, and both variants segregated in a sibling with similar seizure manifestations but was not reported to have hearing loss at 3 years of age (Ngoh 2017). In addition, the variant was reported in one homozygote individual and h is sibling (Poulat 2015), and one compound heterozygote individual (Ragona 2017) , all presenting with TBC1D24-related seizures, but hearing loss was not reporte d. The p.Glu153Lys variant has been identified in 3/20274 Finnish and 12/110864 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org; dbSNP rs376712059), and has been reported in ClinVar (Variati on ID 207499). Although there is a wide range of clinical features reported for affected individuals that carry this variant, these features are consistent with the phenotypic spectrum associated with TBC1D24-associated disorders. In additi on, the segregation of the variant in similarly affected family members in three unrelated families supports a causative role for the variant. Furthermore, comp utational prediction tools and conservation analysis suggest that the p.Glu153Ly s variant may impact the protein. In summary, although additional studies are r equired to fully establish its clinical significance, this variant is likely pat hogenic. ACMG/AMP Criteria applied: PP1_S, PM3_S, PM2, PM3, PP3, PP4. -

Developmental and epileptic encephalopathy, 1;C3892048:Autosomal dominant nonsyndromic hearing loss 65;CN236805:Caused by mutation in the TBC1 domain family, member 24

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 09, 2023

For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TBC1D24 protein function. ClinVar contains an entry for this variant (Variation ID: 207499). This missense change has been observed in individuals with autosomal recessive TBC1D24-related conditions (PMID: 25769375, 26371875, 28428906). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs376712059, gnomAD 0.01%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 153 of the TBC1D24 protein (p.Glu153Lys). -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 16, 2016

The p.E153K variant (also known as c.457G>A), located in coding exon 1 of the TBC1D24 gene, results from a G to A substitution at nucleotide position 457. The glutamic acid at codon 153 is replaced by lysine, an amino acid with similar properties. This alteration was detected in the homozygous state in two brothers of Algerian descent from a consanguineous family with early onset focal myoclonic fits that evolved to generalized myoclonus, developmental delay, moderate learning concerns, and a diagnosis of familial infantile myoclonic epilepsy; however, TBC1D24 was the only gene analyzed (Poulat AL, Epilepsy Res. 2015 Mar; 111:72-7). In addition, this alteration was detected in trans with another alteration in the TBC1D24 via whole exome sequencing in two siblings with nonsyndromic hearing loss (Bakhchane A, PLoS ONE 2015; 10(9):e0138072). This variant was previously reported in the SNPDatabase as rs376712059. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/12876) total alleles studied and 0.01% (1/8536) European American alleles. Based on data from ExAC, the A allele has an overall frequency of approximately <0.01% (8/104258) total alleles studied (TCGA excluded). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Uncertain

0.030

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.97

M_CAP

Pathogenic

0.57

MetaRNN

Uncertain

0.58

D;D;D;D;D;D;D

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.6

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

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.5

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

Sift

Benign

0.054

T;.;T;.;.;.;D

Sift4G

Uncertain

0.039

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

Polyphen

1.0

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

Vest4

0.91

MVP

0.69

MPC

1.2, 1.5

ClinPred

0.25

GERP RS

5.3

Varity_R

0.33

gMVP

0.81

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