rs747821285

chr16-2496476-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PP3_Strong PP5

The NM_001199107.2(TBC1D24):c.328G>A(p.Gly110Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,458,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G110G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TBC1D24 NM_001199107.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 6.48

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_001199107.2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 16-2496476-G-A is Pathogenic according to our data. Variant chr16-2496476-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 183154.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D24	NM_001199107.2	c.328G>A	p.Gly110Ser	missense_variant	2/8	ENST00000646147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D24	ENST00000646147.1	c.328G>A	p.Gly110Ser	missense_variant	2/8		NM_001199107.2	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245840 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133980

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00000548 AC: 8 AN: 1458606 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 725776

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.00000826 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

DOORS syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Jan 01, 2014	We identified 26 families with DOORS syndrome; each patient had at least 3 of the 5 well-described features of DOORS syndrome, which include deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. A combination of whole-exome sequencing and Sanger sequencing identified homozygous or compound heterozygous pathogenic variants in TBC1D24 in 11 individuals from 9 families. -
Pathogenic, no assertion criteria provided	literature only	Division of Medical Genetics; Sainte-Justine Hospital	Dec 22, 2014	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 22, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28428906, 28606688, 24291220) -

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

Invitae

Nov 24, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 110 of the TBC1D24 protein (p.Gly110Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with DOORS syndrome (Deafness, Onychodystrophy, Osteodystrophy, mental Retardation, and Seizures) (PMID: 24291220; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 183154). 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	Pathogenic	0.83
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.5	L;L;L;.;.;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.6	D;.;D;.;.;.;D
Sift	Benign	0.033	D;.;D;.;.;.;D
Sift4G	Benign	0.095	T;.;T;.;.;T;T
Polyphen		1.0	D;D;D;.;.;D;.
Vest4		0.15
MutPred		0.81		Loss of methylation at R109 (P = 0.0455);Loss of methylation at R109 (P = 0.0455);Loss of methylation at R109 (P = 0.0455);Loss of methylation at R109 (P = 0.0455);Loss of methylation at R109 (P = 0.0455);Loss of methylation at R109 (P = 0.0455);Loss of methylation at R109 (P = 0.0455);
MVP		0.80
MPC		1.0, 1.3
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.40
gMVP		0.82

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: rs747821285; hg19: chr16-2546477; COSMIC: COSV99565226; COSMIC: COSV99565226;