chr16-2496267-G-A

Variant names:

• chr16-2496267-G-A
• rs760474458
• NM_001199107.2:c.119G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_001199107.2(TBC1D24):​c.119G>A​(p.Arg40His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,398 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TBC1D24 NM_001199107.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.59
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• DOORS syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, PanelApp Australia, G2P
• familial infantile myoclonic epilepsy

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet
• autosomal dominant nonsyndromic hearing loss 65

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• focal epilepsy-intellectual disability-cerebro-cerebellar malformation

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• progressive myoclonic epilepsy with dystonia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 86

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000260272 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001199107.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2496267-G-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 183152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 16-2496267-G-A is Pathogenic according to our data. Variant chr16-2496267-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 856852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2496267-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 856852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2496267-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 856852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2496267-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 856852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2496267-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 856852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2496267-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 856852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2496267-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 856852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2496267-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 856852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2496267-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 856852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2496267-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 856852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2496267-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 856852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2496267-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 856852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2496267-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 856852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2496267-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 856852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2496267-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 856852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2496267-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 856852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D24	NM_001199107.2	c.119G>A	p.Arg40His	missense_variant	Exon 2 of 8	ENST00000646147.1	NP_001186036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D24	ENST00000646147.1	c.119G>A	p.Arg40His	missense_variant	Exon 2 of 8		NM_001199107.2	ENSP00000494678.1
ENSG00000260272	ENST00000564543.1	c.119G>A	p.Arg40His	missense_variant	Exon 1 of 3	2		ENSP00000455547.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 249018 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461398 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727016

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Jan 31, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30180405, 31112829, 33333793, 34120799) -

Abnormality of the nervous system Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 1;C3892048:Autosomal dominant nonsyndromic hearing loss 65;CN236805:Caused by mutation in the TBC1 domain family, member 24 Pathogenic:1

Mar 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 40 of the TBC1D24 protein (p.Arg40His). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of DOORS syndrome (PMID: 31112829, 33333793; 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: 856852). 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 expected to disrupt TBC1D24 protein function. This variant disrupts the p.Arg40 amino acid residue in TBC1D24. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24291220, 27669036, 31257402; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	.;T;T;.;.;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;D;D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.5	M;M;M;.;.;M;.
PhyloP100		9.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.3	D;.;D;D;.;.;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;.;D;D;.;.;D
Sift4G	Pathogenic	0.0	D;.;D;D;.;D;D
Polyphen		1.0	D;D;D;.;.;D;.
Vest4		0.77
MutPred		0.84		Loss of MoRF binding (P = 0.0152);Loss of MoRF binding (P = 0.0152);Loss of MoRF binding (P = 0.0152);Loss of MoRF binding (P = 0.0152);Loss of MoRF binding (P = 0.0152);Loss of MoRF binding (P = 0.0152);Loss of MoRF binding (P = 0.0152);
MVP		0.94
MPC		1.2, 1.6
ClinPred		1.0	D
GERP RS		5.6
PromoterAI		-0.0097	Neutral
Varity_R		0.71
gMVP		0.86
Mutation Taster		=11/89	disease causing

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

Other links and lift over

dbSNP: rs760474458; hg19: chr16-2546268; COSMIC: COSV99565217; COSMIC: COSV99565217;