TBC1D1

protein-coding

TBC1 domain family member 1

Gene summary

TBC1D1 is the founding member of a family of proteins sharing a 180- to 200-amino acid TBC domain presumed to have a role in regulating cell growth and differentiation. These proteins share significant homology with TRE2 (USP6; MIM 604334), yeast Bub2, and CDC16 (MIM 603461) (White et al., 2000 [PubMed 10965142]).[supplied by OMIM, Mar 2008]

MANE transcript

NM_001396959.1

Inheritance

ClinVar variants

U:195B:50

Top phenotype

non-syndromic renal or urinary tract malformation

gnomAD constraint

pLI —, LoF o/e 0.52

Max pathogenic AF

—

Genomic locus

chr4:37,891,084-38,139,175

External References & Databases

Ensembl (ENSG00000065882)

Transcript & Mutation Effects

hg38 • Region Span ~248.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

non-syndromic renal or urinary tract malformationSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0019720

Submitter: PanelApp Australia

congenital anomaly of kidney and urinary tractLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019719

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TBC1D1 variants in ClinVar

6 Conditions Cataloged

Inborn genetic diseasesTotal: 180

TBC1D1-related disorderTotal: 45

not specifiedTotal: 44

not providedTotal: 20

Congenital anomaly of kidney and urinary tractTotal: 1

Non-syndromic renal or urinary tract malformationTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001396959.1. 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			7 clinvar	22 clinvar	3 clinvar	32
missense			176 clinvar	23 clinvar	1 clinvar	200
nonsense			2 clinvar			2
start loss						0
frameshift			3 clinvar	1 clinvar		4
splice donor/acceptor (+/-2bp)			7 clinvar			7
Total	0	0	195	46	4	245

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 82 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001396959.1	RefSeq	NP_001383888.1	21	MANE Select
ENST00000698857.1	Ensembl	ENSP00000513987.1	21	MANE Select
NM_001253912.2	RefSeq	NP_001240841.1	20	Standard
NM_001253913.2	RefSeq	NP_001240842.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

AMPK signaling pathway - Homo sapiens (human)
Focal Adhesion-PI3K-Akt-mTOR-signaling pathway
Vesicle-mediated transport
Membrane Trafficking
Translocation of GLUT4 to the plasma membrane

Biological Process

intracellular protein transport
regulation of protein localization
membrane organization
activation of GTPase activity
regulation of cilium assembly

Molecular Function

GTPase activator activity
protein binding
Rab GTPase binding

Cellular Component

nucleus
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261439
Coding exons: 19
Length: 248089
Individuals with no LoFs: 125641
Homozygous LoFs: 1
Heterozygous LoFs: 106
Defined: 125748
p: 0.000426

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.755	623	678	0.918	0.0000411	7685
Missense (PolyPhen)		205	240.33	0.853		2691
Synonymous	-0.0361	279	278	1.00	0.0000189	2229
Loss of Function	3.46	31	59.9	0.518	0.00000352	634

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00074	0.00074	rare
Latino/Admixed American	0.00061	0.00061	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00077	0.00071	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00044	0.00043	rare
South Asian	0.00024	0.00020	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May act as a GTPase-activating protein for Rab family protein(s). May play a role in the cell cycle and differentiation of various tissues. Involved in the trafficking and translocation of GLUT4-containing vesicles and insulin-stimulated glucose uptake into cells (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.206

Intolerance Scores

LoFtool: 0.881
RVIS EVS: 0.01
RVIS percentile EVS: 54.16

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.615

Gene Damage Prediction

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