13-75288954-C-A

Variant names:

• chr13-75288954-C-A
• NM_014832.5:c.3643G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014832.5(TBC1D4):​c.3643G>T​(p.Asp1215Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBC1D4 NM_014832.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50

Genes affected

TBC1D4 (HGNC:19165): (TBC1 domain family member 4) This gene is a member of the Tre-2/BUB2/CDC16 domain family. The protein encoded by this gene is a Rab-GTPase-activating protein, and contains two phopshotyrosine-binding domains (PTB1 and PTB2), a calmodulin-binding domain (CBD), a Rab-GTPase domain, and multiple AKT phosphomotifs. This protein is thought to play an important role in glucose homeostasis by regulating the insulin-dependent trafficking of the glucose transporter 4 (GLUT4), important for removing glucose from the bloodstream into skeletal muscle and fat tissues. Reduced expression of this gene results in an increase in GLUT4 levels at the plasma membrane, suggesting that this protein is important in intracellular retention of GLUT4 under basal conditions. When exposed to insulin, this protein is phosphorylated, dissociates from GLUT4 vesicles, resulting in increased GLUT4 at the cell surface, and enhanced glucose transport. Phosphorylation of this protein by AKT is required for proper translocation of GLUT4 to the cell surface. Individuals homozygous for a mutation in this gene are at higher risk for type 2 diabetes and have higher levels of circulating glucose and insulin levels after glucose ingestion. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D4	NM_014832.5	c.3643G>T	p.Asp1215Tyr	missense_variant	Exon 20 of 21	ENST00000377636.8	NP_055647.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D4	ENST00000377636.8	c.3643G>T	p.Asp1215Tyr	missense_variant	Exon 20 of 21	2	NM_014832.5	ENSP00000366863.3
TBC1D4	ENST00000431480.6	c.3619G>T	p.Asp1207Tyr	missense_variant	Exon 19 of 20	1		ENSP00000395986.2
TBC1D4	ENST00000377625.6	c.3454G>T	p.Asp1152Tyr	missense_variant	Exon 18 of 19	1		ENSP00000366852.2
TBC1D4	ENST00000648194.1	c.2911G>T	p.Asp971Tyr	missense_variant	Exon 19 of 20			ENSP00000496983.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3643G>T (p.D1215Y) alteration is located in exon 20 (coding exon 20) of the TBC1D4 gene. This alteration results from a G to T substitution at nucleotide position 3643, causing the aspartic acid (D) at amino acid position 1215 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	.;.;.;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.60	D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.6	.;.;.;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.5	.;D;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.012	.;D;D;D
Sift4G	Uncertain	0.012	.;D;D;D
Polyphen		0.99, 1.0, 1.0	.;D;D;D
Vest4		0.63, 0.70, 0.60
MutPred		0.35		.;.;.;Gain of catalytic residue at M1214 (P = 0.0143);
MVP		0.63
MPC		1.1
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.57
gMVP		0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-75863090; COSMIC: COSV66490407;