TBC1D4

Chr 13

TBC1 domain family member 4

Also known as: AS160, NIDDM5

NCBI Gene: 9882 ENSG00000136111 UniProt: O60343

The protein functions as a Rab-GTPase-activating protein that regulates insulin-dependent trafficking of the glucose transporter GLUT4, controlling glucose uptake into skeletal muscle and fat tissues. Homozygous mutations cause increased risk for type 2 diabetes with elevated circulating glucose and insulin levels following glucose ingestion, following autosomal recessive inheritance. The gene shows very low constraint against loss-of-function variants, consistent with a recessive disorder pattern.

ResearchSummary from RefSeq, UniProt

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]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtType 2 diabetes mellitus 5

Active trials

Pubs (1 yr)

—

P/LP submissions

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P/LP missense

0.92

LOEUF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.92LOEUF

pLI 0.000

Z-score 2.11

OE 0.72 (0.56–0.92)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.70Z-score

OE missense 0.93 (0.87–0.99)

649 obs / 701.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.72 (0.56–0.92)

0≤0.351.4

Missense OE?0.93 (0.87–0.99)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 46 / 64.3Missense obs/exp: 649 / 701.1Syn Z: -0.36

Background carrier burden — how many people carry a rare variant somewhere in TBC1D4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 42

1,594 rare PASS variants

Rare truncating (LoF)

1 in 640

263 rare PASS variants

Rare synonymous (reference)

1 in 66

676 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TBC1D4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 67	1 in 930
South Asian	~43k	1 in 43	1 in 540
Remaining (unassigned)	~30k	1 in 38	1 in 620
European (Finnish)	~27k	1 in 150	1 in 860
Admixed American	~22k	1 in 42	1 in 470
African / African American	~21k	1 in 37	1 in 820
East Asian	~20k	1 in 40	1 in 310
Ashkenazi Jewish	~13k	1 in 79	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 32	≈ 1 in 960

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 21 coding exons well covered in gnomAD exomes and genomes.? see exons ↓