UGT1A4

protein-coding

UDP glucuronosyltransferase family 1 member A4, the group of UDP glucuronosyltransferases

Gene summary

This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. This enzyme has some glucuronidase activity towards bilirubin, although is is more active on amines, steroids, and sapogenins. [provided by RefSeq, Jul 2008]

MANE transcript

NM_007120.3

Inheritance

—

ClinVar variants

P:48U:120B:42

Top phenotype

Gilbert syndrome

gnomAD constraint

pLI —, LoF o/e 0.7

Max pathogenic AF

—

Genomic locus

chr2:233,718,736-233,773,300

External References & Databases

Ensembl (ENSG00000244474)

Transcript & Mutation Effects

hg38 • Region Span ~54.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UGT1A4 variants in ClinVar

15 Conditions Cataloged

not providedTotal: 269

not specifiedTotal: 116

Gilbert syndromeTotal: 93

UGT1A1-related disorderTotal: 92

Lucey-Driscoll syndromeTotal: 77

Crigler-Najjar syndrome type 1Total: 65

Crigler-Najjar syndrome, type IITotal: 58

Crigler-Najjar syndromeTotal: 40

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007120.3. 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			2 clinvar	33 clinvar	1 clinvar	36
missense	5 clinvar	19 clinvar	116 clinvar	8 clinvar		148
nonsense	4 clinvar	3 clinvar	1 clinvar			8
start loss						0
frameshift	6 clinvar	5 clinvar				11
splice donor/acceptor (+/-2bp)	2 clinvar	4 clinvar	1 clinvar			7
Total	17	31	120	41	1	210

Highest pathogenic variant AF is 0.00048507

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007120.3	RefSeq	NP_009051.1	5	MANE Select
ENST00000373409.8	Ensembl	ENSP00000362508.4	5	MANE Select
ENST00000450233.1	Ensembl	ENSP00000408608.1	5	Standard
ENST00000979156.1	Ensembl	ENSP00000648973.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Benzodiazepine Pathway, Pharmacokinetics
Retinol metabolism - Homo sapiens (human)
Steroid hormone biosynthesis - Homo sapiens (human)
nicotine degradation III
Metabolism of xenobiotics by cytochrome P450 - Homo sapiens (human)

Biological Process

bilirubin conjugation
heme catabolic process
cellular glucuronidation
flavonoid glucuronidation
xenobiotic glucuronidation

Molecular Function

retinoic acid binding
UDP-glycosyltransferase activity
glucuronosyltransferase activity
protein homodimerization activity
protein heterodimerization activity

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
integral component of membrane
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000373409
Coding exons: 5
Length: 54522
Individuals with no LoFs: 125577
Homozygous LoFs: 0
Heterozygous LoFs: 171
Defined: 125748
p: 0.000680

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.65	378	298	1.27	0.0000178	3483
Missense (PolyPhen)		172	148.57	1.1577		1753
Synonymous	-3.49	169	120	1.40	0.00000764	1085
Loss of Function	1.15	12	17.1	0.700	9.29e-7	209

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.0027	0.0027	notable
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00062	0.00062	rare
South Asian	0.00091	0.00091	rare
Other	0.00081	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX- alpha to form both the IX-alpha-C8 and IX-alpha-C12 monoconjugates and diconjugate. Isoform 2 lacks transferase activity but acts as a negative regulator of isoform 1 (By similarity). {ECO:0000250}.;
Disease: DISEASE: Gilbert syndrome (GILBS) [MIM:143500]: Occurs as a consequence of reduced bilirubin transferase activity and is often detected in young adults with vague non-specific complaints. {ECO:0000269|PubMed:17496722}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Crigler-Najjar syndrome 1 (CN1) [MIM:218800]: Patients have severe hyperbilirubinemia and usually die of kernicterus (bilirubin accumulation in the basal ganglia and brainstem nuclei) within the first year of life. CN1 inheritance is autosomal recessive. {ECO:0000269|PubMed:1634050}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Crigler-Najjar syndrome 2 (CN2) [MIM:606785]: Patients have less severe hyperbilirubinemia and usually survive into adulthood without neurologic damage. Phenobarbital, which induces the partially deficient glucuronyl transferase, can diminish the jaundice. CN2 inheritance is autosomal dominant. {ECO:0000269|PubMed:8276413, ECO:0000269|PubMed:8280139}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.581

Intolerance Scores

LoFtool: 0.938
RVIS EVS: 0.18
RVIS percentile EVS: 66.24

Essentials

Essential (CRISPR): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0826

Gene Damage Prediction

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