GeneBe

UGT1A1

protein-coding

UDP glucuronosyltransferase family 1 member A1, 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. The preferred substrate of this enzyme is bilirubin, although it also has moderate activity with simple phenols, flavones, and C18 steroids. Mutations in this gene result in Crigler-Najjar syndromes types I and II and in Gilbert syndrome. [provided by RefSeq, Jul 2008]

Previous symbols:
  • UGT1
  • GNT1

MANE transcript

NM_000463.3

Inheritance

AR, AD

ClinVar variants

P:88U:188B:60

Top phenotype

Crigler-Najjar syndrome, type I; Crigler-Najjar syndrome, type II; Gilbert syndrome

gnomAD constraint

pLI —, LoF o/e 0.86

Max pathogenic AF

—

Genomic locus

chr2:233,760,270-233,773,300

External References & Databases

Ensembl (ENSG00000241635)NCBI Gene (54658)OMIM (191740)HGNC:12530GenCCUniProt (P22309)AlphaFoldClinVar (UGT1A1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~13.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Crigler-Najjar syndrome type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0021020

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Crigler-Najjar syndrome type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011725

Submitter: Ambry Genetics

Crigler-Najjar syndrome type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0021020

Submitter: G2P

Crigler-Najjar syndrome type 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011725

Submitter: Orphanet

Crigler-Najjar syndrome type 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0021020

Submitter: Orphanet

Crigler-Najjar syndrome type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0021020

Submitter: PanelApp Australia

Gilbert syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007745

Submitter: Labcorp Genetics (formerly Invitae)

Crigler-Najjar syndrome type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0021020

Submitter: Ambry Genetics

Crigler-Najjar syndrome type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011725

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Crigler-Najjar syndrome, type I; Crigler-Najjar syndrome, type II; Gilbert syndromeAD/AR

Manifestation: Gastrointestinal

Intervention: Gastrointestinal; Pharmacogenomic

Rationale: In CNI, phototherapy (or other interventions, such as plasmapharesis), followed by liver transplantation may be beneficial; In CNII, not all individuals have severe forms of disease necessitating treatment, but patients with severe forms typically respond to phenobarbital treatment; Knowledge of the cause of jaundice even in less severe cases can help avoid prolonged etiologic work-ups; While Gilbert syndrome is not as severe as other disorders of hyperbilirubinemia, drug metabolism related to certain medications (eg, acetaminophen, atazanavir, irinotecan) imay be affected, and medication and dosing choice may be beneficial

Refs: 12983120; 5685361; 805737; 3546653; 1734381; 1531971; 8276413; 7989595; 7565971; 8528206; 8690398; 9413009; 9580649; 9621515; 10412811; 11003624; 11061796; 11316168; 11370628; 11906189; 16712705; 18518849; 22676194; 22710376; 23099197; 23162302; 23241680; 23279026; 23403257; 23430851; 23926009; 23992562; 24065680Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UGT1A1 variants in ClinVar

15 Conditions Cataloged
not providedTotal: 250
Gilbert syndromeTotal: 92
UGT1A1-related disorderTotal: 85
Lucey-Driscoll syndromeTotal: 77
Crigler-Najjar syndrome type 1Total: 65
Crigler-Najjar syndrome, type IITotal: 58
Crigler-Najjar syndromeTotal: 40
BILIRUBIN, SERUM LEVEL OF, QUANTITATIVE TRAIT LOCUS 1Total: 39

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000463.3. 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.

EffectPLPVUSLBBSum
synonymous
9
clinvar
56
clinvar
1
clinvar
 66
missense
6
clinvar
27
clinvar
178
clinvar
3
clinvar
 214
nonsense
7
clinvar
5
clinvar
1
clinvar
 13
start loss
1
clinvar
 1
frameshift
22
clinvar
12
clinvar
 34
splice donor/acceptor (+/-2bp)
2
clinvar
6
clinvar
 8
Total3751188591336

Highest pathogenic variant AF is 0.00048507

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000463.3RefSeqNP_000454.15MANE Select
ENST00000305208.10EnsemblENSP00000304845.55MANE Select
ENST00000360418.4EnsemblENSP00000353593.35Standard
ENST00000978718.1EnsemblENSP00000648535.15Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Retinol metabolism - Homo sapiens (human)
  • Steroid hormone biosynthesis - Homo sapiens (human)
  • Metabolism of xenobiotics by cytochrome P450 - Homo sapiens (human)
  • Drug metabolism - other enzymes - Homo sapiens (human)
  • Drug metabolism - cytochrome P450 - Homo sapiens (human)

Biological Process

  • liver development
  • bilirubin conjugation
  • acute-phase response
  • response to nutrient
  • steroid metabolic process

Molecular Function

  • retinoic acid binding
  • enzyme inhibitor activity
  • steroid binding
  • UDP-glycosyltransferase activity
  • glucuronosyltransferase activity

Cellular Component

  • endoplasmic reticulum
  • endoplasmic reticulum membrane
  • integral component of plasma membrane
  • endoplasmic reticulum chaperone complex
  • intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000609767
Coding exons
5
Length
155666
Individuals with no LoFs
125278
Homozygous LoFs
2
Heterozygous LoFs
468
Defined
125748
p
0.00187
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-1.353602951.220.00001663508
Missense (PolyPhen)146141.41.03251691
Synonymous-2.821571181.330.000007131068
Loss of Function0.5231517.40.8649.31e-7204

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0130.013notable
Latino/Admixed American0.00120.0012notable
Ashkenazi Jewish0.00600.0059notable
East Asian0.000160.00016rare
Finnish0.00110.0011notable
European (Non-Finnish)0.000960.00096rare
South Asian0.000560.00052rare
Other0.00180.0018notable

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. Is also able to catalyze the glucuronidation of 17beta-estradiol, 17alpha-ethinylestradiol, 1-hydroxypyrene, 4- methylumbelliferone, 1-naphthol, paranitrophenol, scopoletin, and umbelliferone. Isoform 2 lacks transferase activity but acts as a negative regulator of isoform 1. {ECO:0000269|PubMed:18004206, ECO:0000269|PubMed:19545173, ECO:0000269|PubMed:19830808}.;
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:11013440, ECO:0000269|PubMed:12139570, ECO:0000269|PubMed:7715297, ECO:0000269|PubMed:9627603}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Transient familial neonatal hyperbilirubinemia (HBLRTFN) [MIM:237900]: A condition characterized by excessive concentration of bilirubin in the blood, which may lead to jaundice. Breast milk jaundice is a common problem in nursing infants. {ECO:0000269|PubMed:11061796}. Note=The disease may be caused by mutations affecting the gene represented in this entry. The defect has been ascribed to various breast milk substances, but the component or combination of components that is responsible remains unclear. Defects of UGT1A1 are an underlying cause of the prolonged unconjugated hyperbilirubinemia associated with breast milk. One or more components in the milk may trigger the jaundice in infants who have such mutations. Mutations are identical to those detected in patients with Gilbert syndrome, a risk factor of neonatal non-physiologic hyperbilirubinemia and a genetic factor in fasting hyperbilirubinemia.; 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:11013440, ECO:0000269|PubMed:15712364, ECO:0000269|PubMed:1634050, ECO:0000269|PubMed:17229650, ECO:0000269|PubMed:19830808, ECO:0000269|PubMed:23992562, ECO:0000269|PubMed:7906695, ECO:0000269|PubMed:7989045, ECO:0000269|PubMed:7989595, ECO:0000269|PubMed:8226884}. 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:11013440, ECO:0000269|PubMed:11370628, ECO:0000269|PubMed:12402338, ECO:0000269|PubMed:14550264, ECO:0000269|PubMed:15712364, ECO:0000269|PubMed:17229650, ECO:0000269|PubMed:18004206, ECO:0000269|PubMed:19830808, ECO:0000269|PubMed:23099197, ECO:0000269|PubMed:23992562, ECO:0000269|PubMed:7989595, ECO:0000269|PubMed:8276413, ECO:0000269|PubMed:8280139, ECO:0000269|PubMed:8706880, ECO:0000269|PubMed:9621515, ECO:0000269|PubMed:9639672}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.581

Intolerance Scores

LoFtool
0.881
RVIS EVS
-0.56
RVIS percentile EVS
19.73

Essentials

Essential (CRISPR)
N
Indispensability pred.
N
Indispensability score
0.0320

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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