rs141399869

chr16-2500292-G-Achr16-2500292-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001199107.2(TBC1D24):c.1327G>A(p.Glu443Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000296 in 1,609,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. E443Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: TBC1D24 NM_001199107.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 7.68

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01258707).
• BP6: Variant 16-2500292-G-A is Benign according to our data. Variant chr16-2500292-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 208413.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Benign=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00148 (225/152254) while in subpopulation AFR AF= 0.00518 (215/41542). AF 95% confidence interval is 0.00461. There are 0 homozygotes in gnomad4. There are 102 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D24	NM_001199107.2	c.1327G>A	p.Glu443Lys	missense_variant	7/8	ENST00000646147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D24	ENST00000646147.1	c.1327G>A	p.Glu443Lys	missense_variant	7/8		NM_001199107.2	A1

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 225 AN: 152136 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00519

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000360 AC: 84 AN: 233640 Hom.: 0 AF XY: 0.000312 AC XY: 40 AN XY: 128056

Gnomad AFR exome AF: 0.00452

Gnomad AMR exome AF: 0.000206

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000408

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000194

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000172 AC: 251 AN: 1457238 Hom.: 0 Cov.: 33 AF XY: 0.000163 AC XY: 118 AN XY: 724578

Gnomad4 AFR exome AF: 0.00506

Gnomad4 AMR exome AF: 0.000247

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000317

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.000233

GnomAD4 genome AF: 0.00148 AC: 225 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.00137 AC XY: 102 AN XY: 74444

Gnomad4 AFR AF: 0.00518

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000831 Hom.: 0

Bravo AF: 0.00159

ESP6500AA AF: 0.00536 AC: 22

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000422 AC: 51

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 18, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2017	A variant of uncertain significance has been identified in the TBC1D24 gene. The E443K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E443K variant is observed in 34/5,298 (0.6%) alleles from individuals of African background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E443K 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. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 04, 2023	Variant summary: TBC1D24 c.1327G>A (p.Glu443Lys) results in a conservative amino acid change located in the TLDc domain (IPR006571) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 233640 control chromosomes. This frequency does not allow any conclusion about variant significance. To our knowledge, no occurrence of c.1327G>A in individuals affected with TBC1D24-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Five classified the variant as uncertain significance, and one classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Glu443Lys in exon 7 of TBC1D24: This variant is not expected to have clinical si gnificance because it has been identified in 0.5% (22/4106) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs141399869). -

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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Feb 03, 2022

TBC1D24 NM_001199107.1 exon 7 p.Glu443Lys (c.1327G>A): This variant has not been reported in the literature but is present in 0.5% (215/41420) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-2500292-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:208413). Evolutionary conservation for this variant is limited or unavailable; computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2018

The p.E443K variant (also known as c.1327G>A), located in coding exon 6 of the TBC1D24 gene, results from a G to A substitution at nucleotide position 1327. The glutamic acid at codon 443 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 20, 2017

- -

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

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.013	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.2	N;.;N;.;.;.
Sift	Benign	0.26	T;.;T;.;.;.
Sift4G	Uncertain	0.037	D;.;D;.;.;D
Polyphen		0.99	D;D;D;.;.;D
Vest4		0.79
MVP		0.80
MPC		0.52
ClinPred		0.057	T
GERP RS		5.4
Varity_R		0.28
gMVP		0.72

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: rs141399869; hg19: chr16-2550293;