TBC1D4

protein-coding

TBC1 domain family member 4

Gene summary

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]

MANE transcript

NM_014832.5

Inheritance

ClinVar variants

U:187B:26

Top phenotype

Diabetes mellitus, noninsulin-dependent 5

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr13:75,283,503-75,482,169

External References & Databases

Ensembl (ENSG00000136111)

Transcript & Mutation Effects

hg38 • Region Span ~198.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

Clinical Genomic Database (CGD)

Diabetes mellitus, noninsulin-dependent 5AR

Manifestation: Endocrine

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Heterozygous carriers may also display mild effects related to glucose metabolism

Refs: 25043022

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TBC1D4 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 189

TBC1D4-related disorderTotal: 19

not providedTotal: 18

Diabetes mellitus, noninsulin-dependent, 5Total: 3

Insulin resistanceTotal: 1

TYPE 2 DIABETES MELLITUS 5, SUSCEPTIBILITY TOTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014832.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	9 clinvar	2 clinvar	17
missense			174 clinvar	9 clinvar	5 clinvar	188
nonsense			4 clinvar			4
start loss			1 clinvar			1
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar	1 clinvar		3
Total	0	0	187	19	7	213

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014832.5	RefSeq	NP_055647.2	21	MANE Select
ENST00000377636.8	Ensembl	ENSP00000366863.3	21	MANE Select
NM_001286658.2	RefSeq	NP_001273587.1	20	Standard
NM_001286659.2	RefSeq	NP_001273588.1	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Insulin resistance - Homo sapiens (human)
Thyroid hormone signaling pathway - Homo sapiens (human)
Insulin Signaling
Vesicle-mediated transport
Membrane Trafficking

Biological Process

intracellular protein transport
vesicle-mediated transport
negative regulation of vesicle fusion
cellular response to insulin stimulus
activation of GTPase activity

Molecular Function

GTPase activator activity
Rab GTPase binding

Cellular Component

cytosol
vesicle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000377636
Coding exons: 21
Length: 197443
Individuals with no LoFs: 124613
Homozygous LoFs: 1
Heterozygous LoFs: 204
Defined: 124818
p: 0.000822

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.700	649	701	0.926	0.0000397	8506
Missense (PolyPhen)		274	308.46	0.88828		3848
Synonymous	-0.364	294	286	1.03	0.0000171	2494
Loss of Function	2.11	46	64.3	0.716	0.00000341	746

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0067	0.0066	notable
Latino/Admixed American	0.00076	0.00075	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00039	0.00039	rare
Finnish	0.00042	0.00042	rare
European (Non-Finnish)	0.00040	0.00040	rare
South Asian	0.00036	0.00036	rare
Other	0.00066	0.00066	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May act as a GTPase-activating protein for RAB2A, RAB8A, RAB10 and RAB14. Isoform 2 promotes insulin-induced glucose transporter SLC2A4/GLUT4 translocation at the plasma membrane, thus increasing glucose uptake. {ECO:0000269|PubMed:15971998, ECO:0000269|PubMed:18771725, ECO:0000269|PubMed:22908308}.;
Disease: DISEASE: Diabetes mellitus, non-insulin-dependent, 5 (NIDDM5) [MIM:616087]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:25043022}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.106

Intolerance Scores

LoFtool: 0.771
RVIS EVS: 1.03
RVIS percentile EVS: 91.12

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.631

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium