16-2496977-G-T

Position:

chr16-2496977-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001199107.2(TBC1D24):c.829G>T(p.Ala277Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

TBC1D24
NM_001199107.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.38

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14119425).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D24	NM_001199107.2 link	c.829G>T	p.Ala277Ser	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 link	c.829G>T	p.Ala277Ser	missense_variant	2/8		NM_001199107.2	ENSP00000494678.1		Q9ULP9-1
ENSG00000260272	ENST00000564543.1 link	c.829G>T	p.Ala277Ser	missense_variant	1/3	2		ENSP00000455547.1		H3BQ06

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249414

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135354

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461610

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 17, 2017

A variant of uncertain significance has been identified in the TBC1D24 gene. The A277S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A277S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A277S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

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

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 277 of the TBC1D24 protein (p.Ala277Ser). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 423702). 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%. 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.0012

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

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.79

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

M_CAP

Benign

0.0081

MetaRNN

Benign

0.14

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;L;L;.;.;L;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.26

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

REVEL

Benign

0.052

Sift

Benign

0.39

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

Sift4G

Benign

0.43

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

Polyphen

0.54

P;B;B;.;.;P;.

Vest4

0.097

MutPred

0.42

Gain of phosphorylation at A277 (P = 0.032);Gain of phosphorylation at A277 (P = 0.032);Gain of phosphorylation at A277 (P = 0.032);Gain of phosphorylation at A277 (P = 0.032);Gain of phosphorylation at A277 (P = 0.032);Gain of phosphorylation at A277 (P = 0.032);Gain of phosphorylation at A277 (P = 0.032);

MVP

0.55

MPC

0.31, 0.50

ClinPred

0.096

GERP RS

3.2

Varity_R

0.039

gMVP

0.25

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