rs72768728

Positions:

• chr16-2497033-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001199107.2(TBC1D24):​c.885C>G​(p.Phe295Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00927 in 1,613,604 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0096 (93 hom.)
• Consequence: TBC1D24 NM_001199107.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.710

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001199107.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.00785768).
• BP6: Variant 16-2497033-C-G is Benign according to our data. Variant chr16-2497033-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 139396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2497033-C-G is described in Lovd as [Likely_benign]. Variant chr16-2497033-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00578 (880/152370) while in subpopulation NFE AF= 0.011 (748/68032). AF 95% confidence interval is 0.0103. There are 4 homozygotes in gnomad4. There are 390 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D24	NM_001199107.2	c.885C>G	p.Phe295Leu	missense_variant	2/8	ENST00000646147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D24	ENST00000646147.1	c.885C>G	p.Phe295Leu	missense_variant	2/8		NM_001199107.2	A1

Frequencies

GnomAD3 genomes AF: 0.00578 AC: 880 AN: 152252 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00532 AC: 1322 AN: 248578 Hom.: 6 AF XY: 0.00552 AC XY: 745 AN XY: 134978

Gnomad AFR exome AF: 0.00162

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000752

Gnomad FIN exome AF: 0.000523

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00397

GnomAD4 exome AF: 0.00964 AC: 14086 AN: 1461234 Hom.: 93 Cov.: 31 AF XY: 0.00930 AC XY: 6764 AN XY: 726958

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000649

Gnomad4 FIN exome AF: 0.000815

Gnomad4 NFE exome AF: 0.0121

Gnomad4 OTH exome AF: 0.00604

GnomAD4 genome AF: 0.00578 AC: 880 AN: 152370 Hom.: 4 Cov.: 33 AF XY: 0.00523 AC XY: 390 AN XY: 74514

Gnomad4 AFR AF: 0.00197

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00785 Hom.: 2

Bravo AF: 0.00560

TwinsUK AF: 0.0124 AC: 46

ALSPAC AF: 0.0114 AC: 44

ESP6500AA AF: 0.00210 AC: 9

ESP6500EA AF: 0.0114 AC: 97

ExAC AF: 0.00556 AC: 674

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.00845

EpiControl AF: 0.0106

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 18, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Phe295Leu in exon 2 of TBC1D24: This variant is not expected to have clinical si gnificance because it has been identified in 1.1% (97/8510) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs72768728). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	TBC1D24: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 26, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Familial infantile myoclonic epilepsy Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2017

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

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Benign	0.92
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.83	D
MetaRNN	Benign	0.0079	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.96	L;L;L;.;.;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.45	N;.;N;.;.;.;N
Sift	Benign	1.0	T;.;T;.;.;.;T
Sift4G	Benign	0.47	T;.;T;.;.;T;T
Polyphen		0.088	B;B;B;.;.;B;.
Vest4		0.36
MutPred		0.56		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP		0.45
MPC		0.41, 0.70
ClinPred		0.0035	T
GERP RS		-0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.092
gMVP		0.65

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: rs72768728; hg19: chr16-2547034;