rs200926225

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS1

The NM_001199107.2(TBC1D24):c.493G>A(p.Gly165Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000412 in 1,612,410 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

TBC1D24
NM_001199107.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 1.11

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 Benign. Variant got -7 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=0.003846109).

BP6

Variant 16-2496641-G-A is Benign according to our data. Variant chr16-2496641-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 207484.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=3, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0015 (229/152354) while in subpopulation AFR AF= 0.0044 (183/41578). AF 95% confidence interval is 0.00388. There are 0 homozygotes in gnomad4. There are 122 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	Protein	UniProt
TBC1D24	NM_001199107.2 linkuse as main transcript	c.493G>A	p.Gly165Ser	missense_variant	2/8	ENST00000646147.1	NP_001186036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D24	ENST00000646147.1 linkuse as main transcript	c.493G>A	p.Gly165Ser	missense_variant	2/8		NM_001199107.2	ENSP00000494678	A1	Q9ULP9-1

Frequencies

GnomAD3 genomes

AF:

0.00146

AC:

223

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00427

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000621

AC:

154

AN:

247984

Hom.:

AF XY:

0.000527

AC XY:

AN XY:

134814

show subpopulations

Gnomad AFR exome

AF:

0.00545

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00438

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000497

GnomAD4 exome

AF:

0.000299

AC:

436

AN:

1460056

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

205

AN XY:

726412

show subpopulations

Gnomad4 AFR exome

AF:

0.00454

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00402

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000103

Gnomad4 OTH exome

AF:

0.000845

GnomAD4 genome

AF:

0.00150

AC:

229

AN:

152354

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

122

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00440

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.00548

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000446

Hom.:

Bravo

AF:

0.00148

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00416

AC:

ESP6500EA

AF:

0.000468

AC:

ExAC

AF:

0.000660

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 16

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Sep 06, 2016

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 09, 2016

p.Gly165Ser in exon 2 of TBC1D24: This variant is not expected to have clinical significance because it has been identified in 0.5% (51/9574) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200926225). -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

TBC1D24-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 28, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 31, 2020

This variant is associated with the following publications: (PMID: 24291220) -

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 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.77

CADD

Benign

DANN

Benign

0.73

DEOGEN2

Benign

0.0064

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

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.085

LIST_S2

Uncertain

0.88

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

M_CAP

Benign

0.0057

MetaRNN

Benign

0.0038

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

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.28

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

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

0.10

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

REVEL

Benign

0.0030

Sift

Benign

0.76

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

Sift4G

Benign

0.48

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

Polyphen

0.0010

B;B;B;.;.;B;.

Vest4

0.025

MVP

0.27

MPC

0.34, 0.51

ClinPred

0.00040

GERP RS

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.3

Varity_R

0.025

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