16-2496899-T-G

Variant names:

• chr16-2496899-T-G
• rs267607104
• NM_001199107.2:c.751T>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP5

The NM_001199107.2(TBC1D24):​c.751T>G​(p.Phe251Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. F251L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBC1D24 NM_001199107.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.01
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2496899-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 50.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP5: Variant 16-2496899-T-G is Pathogenic according to our data. Variant chr16-2496899-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1326157.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D24	NM_001199107.2	c.751T>G	p.Phe251Val	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.751T>G	p.Phe251Val	missense_variant	Exon 2 of 8		NM_001199107.2	ENSP00000494678.1
ENSG00000260272	ENST00000564543.1	c.751T>G	p.Phe251Val	missense_variant	Exon 1 of 3	2		ENSP00000455547.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Dec 12, 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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 20797691, 32004315)

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

Jun 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant disrupts the p.Phe251 amino acid residue in TBC1D24. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20797691). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 251 of the TBC1D24 protein (p.Phe251Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TBC1D24-related conditions. ClinVar contains an entry for this variant (Variation ID: 1326157). 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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0	.;T;T;.;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.0	.;.;D;D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.64	D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;M;.;.;M;.
PhyloP100		6.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.5	D;.;D;.;.;.;D
REVEL	Benign	0.0
Sift	Uncertain	0.0030	D;.;D;.;.;.;D
Sift4G	Uncertain	0.010	D;.;D;.;.;D;D
Vest4		0.62
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.72
gMVP		0.62

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: rs267607104; hg19: chr16-2546900;