UCP3

protein-coding

uncoupling protein 3, the group of Solute carrier family 25

Gene summary

Mitochondrial uncoupling proteins (UCP) are members of the larger family of mitochondrial anion carrier proteins (MACP). UCPs separate oxidative phosphorylation from ATP synthesis with energy dissipated as heat, also referred to as the mitochondrial proton leak. UCPs facilitate the transfer of anions from the inner to the outer mitochondrial membrane and the return transfer of protons from the outer to the inner mitochondrial membrane. They also reduce the mitochondrial membrane potential in mammalian cells. The different UCPs have tissue-specific expression; this gene is primarily expressed in skeletal muscle. This gene's protein product is postulated to protect mitochondria against lipid-induced oxidative stress. Expression levels of this gene increase when fatty acid supplies to mitochondria exceed their oxidation capacity and the protein enables the export of fatty acids from mitochondria. UCPs contain the three solcar protein domains typically found in MACPs. Two splice variants have been found for this gene.[provided by RefSeq, Nov 2008]

MANE transcript

NM_003356.4

Inheritance

ClinVar variants

U:134B:61

Top phenotype

UCP3-related disorder

gnomAD constraint

pLI —, LoF o/e 1.13

Max pathogenic AF

—

Genomic locus

chr11:74,000,277-74,009,085

External References & Databases

Ensembl (ENSG00000175564)

Transcript & Mutation Effects

hg38 • Region Span ~8.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

inherited obesityLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019182

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UCP3 variants in ClinVar

10 Conditions Cataloged

UCP3-related disorderTotal: 149

not providedTotal: 71

not specifiedTotal: 63

ObesityTotal: 10

Inherited obesityTotal: 6

Obesity, severe, and type II diabetesTotal: 3

Morbid obesityTotal: 1

UCP3 POLYMORPHISM G/ATotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003356.4. 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			1 clinvar	48 clinvar	2 clinvar	51
missense			121 clinvar	7 clinvar	2 clinvar	130
nonsense			1 clinvar	1 clinvar		2
start loss			1 clinvar			1
frameshift			6 clinvar			6
splice donor/acceptor (+/-2bp)			4 clinvar		1 clinvar	5
Total	0	0	134	56	5	195

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003356.4	RefSeq	NP_003347.1	6	MANE Select
ENST00000314032.9	Ensembl	ENSP00000323740.4	6	MANE Select
NM_022803.3	RefSeq	NP_073714.1	5	Standard
ENST00000426995.2	Ensembl	ENSP00000392143.2	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Electron Transport Chain
Energy Metabolism
Exercise-induced Circadian Regulation
The citric acid (TCA) cycle and respiratory electron transport
Metabolism

Biological Process

response to superoxide
response to hypoxia
lipid metabolic process
fatty acid metabolic process
aging

Molecular Function

transporter activity
protein binding
oxidative phosphorylation uncoupler activity

Cellular Component

mitochondrion
mitochondrial inner membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000314032
Coding exons: 6
Length: 9155
Individuals with no LoFs: 124047
Homozygous LoFs: 54
Heterozygous LoFs: 1647
Defined: 125748
p: 0.00679

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.306	218	206	1.06	0.0000130	2015
Missense (PolyPhen)		79	75.707	1.0435		672
Synonymous	-1.29	101	85.8	1.18	0.00000595	655
Loss of Function	-0.407	13	11.5	1.13	5.73e-7	140

Population LoF Frequency

Population	CAF	p-value	Status
African	0.091	0.089	notable
Latino/Admixed American	0.0058	0.0055	notable
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.00055	0.00054	rare
South Asian	0.00088	0.00085	rare
Other	0.0052	0.0047	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: UCP are mitochondrial transporter proteins that create proton leaks across the inner mitochondrial membrane, thus uncoupling oxidative phosphorylation. As a result, energy is dissipated in the form of heat. May play a role in the modulation of tissue respiratory control. Participates in thermogenesis and energy balance.;

Recessive Scores

pRec: 0.329

Intolerance Scores

LoFtool: 0.358
RVIS EVS: 0.33
RVIS percentile EVS: 73.61

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.979

Gene Damage Prediction

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