rs12373107

Positions:

• chr16-2500405-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001199107.2(TBC1D24):​c.1440G>A​(p.Ser480Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0284 in 1,601,820 control chromosomes in the GnomAD database, including 874 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (70 hom., cov: 33)
  • Exomes 𝑓: 0.029 (804 hom.)
• Consequence: TBC1D24 NM_001199107.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -6.62

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]

ENSG00000260272 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-2500405-G-A is Benign according to our data. Variant chr16-2500405-G-A is described in ClinVar as [Benign]. Clinvar id is 130536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2500405-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-6.62 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.064 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D24	NM_001199107.2	c.1440G>A	p.Ser480Ser	synonymous_variant	7/8	ENST00000646147.1	NP_001186036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D24	ENST00000646147.1	c.1440G>A	p.Ser480Ser	synonymous_variant	7/8		NM_001199107.2	ENSP00000494678.1
ENSG00000260272	ENST00000564543.1	c.965+3292G>A		intron_variant		2		ENSP00000455547.1

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3532 AN: 152148 Hom.: 70 Cov.: 33

Gnomad AFR AF: 0.00700

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0674

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.0154

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0263

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.0320 AC: 7039 AN: 219852 Hom.: 231 AF XY: 0.0305 AC XY: 3660 AN XY: 120102

Gnomad AFR exome AF: 0.00777

Gnomad AMR exome AF: 0.0928

Gnomad ASJ exome AF: 0.0196

Gnomad EAS exome AF: 0.000179

Gnomad SAS exome AF: 0.0281

Gnomad FIN exome AF: 0.0136

Gnomad NFE exome AF: 0.0262

Gnomad OTH exome AF: 0.0291

GnomAD4 exome AF: 0.0289 AC: 41889 AN: 1449554 Hom.: 804 Cov.: 33 AF XY: 0.0289 AC XY: 20800 AN XY: 720002

Gnomad4 AFR exome AF: 0.00545

Gnomad4 AMR exome AF: 0.0865

Gnomad4 ASJ exome AF: 0.0187

Gnomad4 EAS exome AF: 0.000179

Gnomad4 SAS exome AF: 0.0301

Gnomad4 FIN exome AF: 0.0157

Gnomad4 NFE exome AF: 0.0294

Gnomad4 OTH exome AF: 0.0244

GnomAD4 genome AF: 0.0232 AC: 3532 AN: 152266 Hom.: 70 Cov.: 33 AF XY: 0.0231 AC XY: 1721 AN XY: 74450

Gnomad4 AFR AF: 0.00698

Gnomad4 AMR AF: 0.0674

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0263

Gnomad4 FIN AF: 0.0154

Gnomad4 NFE AF: 0.0263

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0229 Hom.: 26

Bravo AF: 0.0268

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Ser480Ser in exon 7 of TBC1D24: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 2.6% (222/8400) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs12373107). -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Familial infantile myoclonic epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2016

This alteration is classified as 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. -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.050
DANN	Benign	0.88

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: rs12373107; hg19: chr16-2550406;