TBC1D4

TBC1 domain family member 4

Basic information

Region (hg38): 13:75283502-75482169

Links

ENSG00000136111 ∙ NCBI:9882 ∙ OMIM:612465 ∙ HGNC:19165 ∙ Uniprot:O60343 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Diabetes mellitus, noninsulin-dependent 5	AR	General	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	Endocrine	25043022
Heterozygous carriers may also display mild effects related to glucose metabolism

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TBC1D4 gene.

• not provided (47 variants)
• Inborn genetic diseases (35 variants)
• not specified (27 variants)
• TBC1D4-related condition (2 variants)
• Insulin resistance (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TBC1D4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	2	5	9
missense			40	4	7	51
nonsense						0
start loss			1			1
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)				1		1
splice region					1	1
non coding					34	34
Total	0	0	43	7	46

Variants in TBC1D4

This is a list of pathogenic ClinVar variants found in the TBC1D4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
13-75286668-C-A			Benign (Jun 19, 2021)
13-75286854-G-C		not specified	Uncertain significance (Dec 18, 2023)
13-75286862-T-C		not specified	Likely benign (Oct 05, 2016)
13-75286865-A-G		not specified	Likely benign (-)
13-75286879-G-C		not specified	Likely benign (May 02, 2017)
13-75286927-T-A		not specified	Likely benign (-)
13-75286993-T-A			Benign (Aug 22, 2018)
13-75287038-G-GA		not specified	Benign (Feb 21, 2013)
13-75288980-T-C		not specified	Benign (Sep 05, 2013)
13-75289179-G-C			Benign (Nov 12, 2018)
13-75292148-G-A		not specified	Benign (Jun 09, 2021)
13-75292197-T-C		TBC1D4-related disorder	Likely benign (Sep 25, 2020)
13-75292232-A-G		not specified	Benign (Jul 31, 2018)
13-75292518-T-A			Benign (Jun 19, 2021)
13-75292525-C-T			Benign (Nov 12, 2018)
13-75294562-T-C			Benign (Nov 12, 2018)
13-75294705-C-T			Benign (Nov 12, 2018)
13-75294942-A-T		not specified	Uncertain significance (Mar 04, 2024)
13-75295271-A-T			Benign (Nov 12, 2018)
13-75299338-A-G		not specified	Uncertain significance (Dec 20, 2023)
13-75299364-C-T		Insulin resistance • not specified	Uncertain significance (Jun 21, 2022)
13-75299375-G-T		not specified	Uncertain significance (May 24, 2023)
13-75299455-T-A		not specified	Uncertain significance (Mar 29, 2023)
13-75299651-G-A			Benign (Nov 12, 2018)
13-75302249-C-T		not specified	Uncertain significance (Nov 30, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TBC1D4	protein_coding	protein_coding	ENST00000377636	21	197443

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
8.47e-24	0.481	124613	1	204	124818	0.000822

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.700	649	701	0.926	0.0000397	8506
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00742	0.00736
Ashkenazi Jewish	0.0000993	0.0000993
East Asian	0.000391	0.000389
Finnish	0.000421	0.000417
European (Non-Finnish)	0.000403	0.000397
Middle Eastern	0.000391	0.000389
South Asian	0.000362	0.000360
Other	0.000660	0.000659

dbNSFP

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.
• Pathway: Insulin resistance - Homo sapiens (human);Thyroid hormone signaling pathway - Homo sapiens (human);Insulin Signaling;Vesicle-mediated transport;Membrane Trafficking;Translocation of GLUT4 to the plasma membrane;Insulin-mediated glucose transport;Class I PI3K signaling events mediated by Akt (Consensus)

Recessive Scores

• pRec: 0.106

Intolerance Scores

• loftool: 0.771
• rvis_EVS: 1.03
• rvis_percentile_EVS: 91.12

Haploinsufficiency Scores

• pHI: 0.223
• hipred: Y
• hipred_score: 0.744
• ghis: 0.450

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.631

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tbc1d4
• Phenotype: growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; muscle phenotype; cellular phenotype; homeostasis/metabolism phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hearing/vestibular/ear phenotype; immune system phenotype

Gene ontology

• Biological process: intracellular protein transport;vesicle-mediated transport;negative regulation of vesicle fusion;cellular response to insulin stimulus;activation of GTPase activity
• Cellular component: cytosol;vesicle
• Molecular function: GTPase activator activity;Rab GTPase binding