2-233768234-C-T
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_007120.3(UGT1A4):c.1102C>T(p.Arg368Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000051 ( 0 hom. )
Consequence
UGT1A4
NM_007120.3 missense
NM_007120.3 missense
Scores
6
10
3
Clinical Significance
Conservation
PhyloP100: 2.72
Genes affected
UGT1A4 (HGNC:12536): (UDP glucuronosyltransferase family 1 member A4) 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]
UGT1A5 (HGNC:12537): (UDP glucuronosyltransferase family 1 member A5) 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. [provided by RefSeq, Jul 2008]
UGT1A3 (HGNC:12535): (UDP glucuronosyltransferase family 1 member A3) 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. Substrates of this enzyme include estrone, 2-hydroxyestrone, and metabolites of benzo alpha-pyrene. [provided by RefSeq, Jul 2008]
UGT1A1 (HGNC:12530): (UDP glucuronosyltransferase family 1 member A1) 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]
UGT1A6 (HGNC:12538): (UDP glucuronosyltransferase family 1 member A6) 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 enzyme encoded by this gene is active on phenolic and planar compounds. Alternative splicing in the unique 5' end of this gene results in two transcript variants. [provided by RefSeq, Jul 2008]
UGT1A10 (HGNC:12531): (UDP glucuronosyltransferase family 1 member A10) 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 enzyme encoded by this gene has glucuronidase activity on mycophenolic acid, coumarins, and quinolines. [provided by RefSeq, Jul 2008]
UGT1A8 (HGNC:12540): (UDP glucuronosyltransferase family 1 member A8) 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 enzyme encoded by this gene has glucuronidase activity with many substrates including coumarins, phenols, anthraquinones, flavones, and some opioids. [provided by RefSeq, Jul 2008]
UGT1A7 (HGNC:12539): (UDP glucuronosyltransferase family 1 member A7) 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 enzyme encoded by this gene has moderate glucuronidase activity with phenols. [provided by RefSeq, Jul 2008]
UGT1A9 (HGNC:12541): (UDP glucuronosyltransferase family 1 member A9) 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 enzyme encoded by this gene is active on phenols. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.782
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| UGT1A4 | NM_007120.3 | c.1102C>T | p.Arg368Cys | missense_variant | 4/5 | ENST00000373409.8 | NP_009051.1 | |
| UGT1A5 | NM_019078.2 | c.1102C>T | p.Arg368Cys | missense_variant | 4/5 | ENST00000373414.4 | NP_061951.1 | |
| UGT1A3 | NM_019093.4 | c.1102C>T | p.Arg368Cys | missense_variant | 4/5 | ENST00000482026.6 | NP_061966.1 | |
| UGT1A1 | NM_000463.3 | c.1099C>T | p.Arg367Cys | missense_variant | 4/5 | ENST00000305208.10 | NP_000454.1 | |
| UGT1A6 | NM_001072.4 | c.1096C>T | p.Arg366Cys | missense_variant | 4/5 | ENST00000305139.11 | NP_001063.2 | |
| UGT1A10 | NM_019075.4 | c.1090C>T | p.Arg364Cys | missense_variant | 4/5 | ENST00000344644.10 | NP_061948.1 | |
| UGT1A8 | NM_019076.5 | c.1090C>T | p.Arg364Cys | missense_variant | 4/5 | ENST00000373450.5 | NP_061949.3 | |
| UGT1A7 | NM_019077.3 | c.1090C>T | p.Arg364Cys | missense_variant | 4/5 | ENST00000373426.4 | NP_061950.2 | |
| UGT1A9 | NM_021027.3 | c.1090C>T | p.Arg364Cys | missense_variant | 4/5 | ENST00000354728.5 | NP_066307.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| UGT1A4 | ENST00000373409.8 | c.1102C>T | p.Arg368Cys | missense_variant | 4/5 | 1 | NM_007120.3 | ENSP00000362508.4 | ||
| UGT1A5 | ENST00000373414.4 | c.1102C>T | p.Arg368Cys | missense_variant | 4/5 | 1 | NM_019078.2 | ENSP00000362513.3 | ||
| UGT1A3 | ENST00000482026.6 | c.1102C>T | p.Arg368Cys | missense_variant | 4/5 | 1 | NM_019093.4 | ENSP00000418532.1 | ||
| UGT1A1 | ENST00000305208.10 | c.1099C>T | p.Arg367Cys | missense_variant | 4/5 | 1 | NM_000463.3 | ENSP00000304845.5 | ||
| UGT1A6 | ENST00000305139.11 | c.1096C>T | p.Arg366Cys | missense_variant | 4/5 | 1 | NM_001072.4 | ENSP00000303174.6 | ||
| UGT1A10 | ENST00000344644.10 | c.1090C>T | p.Arg364Cys | missense_variant | 4/5 | 1 | NM_019075.4 | ENSP00000343838.5 | ||
| UGT1A9 | ENST00000354728.5 | c.1090C>T | p.Arg364Cys | missense_variant | 4/5 | 1 | NM_021027.3 | ENSP00000346768.4 | ||
| UGT1A7 | ENST00000373426.4 | c.1090C>T | p.Arg364Cys | missense_variant | 4/5 | 1 | NM_019077.3 | ENSP00000362525.3 | ||
| UGT1A8 | ENST00000373450.5 | c.1090C>T | p.Arg364Cys | missense_variant | 4/5 | 1 | NM_019076.5 | ENSP00000362549.4 |
Frequencies
GnomAD3 genomes 0.0000657 AC: 10AN: 152152Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000201 AC: 5AN: 249050Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134814
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GnomAD4 exome AF: 0.0000513 AC: 75AN: 1461892Hom.: 0 Cov.: 36 AF XY: 0.0000523 AC XY: 38AN XY: 727246
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GnomAD4 genome 0.0000657 AC: 10AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74340
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 12, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 13, 2020 | The UGT1A1 c.1099C>T; p.Arg367Cys variant (rs55750087) is reported in an infant with neonatal unconjugated hyperbilirubinemia who also carried a pathogenic UGT1A1 on the opposite chromosome (Minucci 2013). Additionally, other variants at this codon (c.1099C>G; p.Arg367Gly and c.1100G>A; p.Arg367His) have been reported in individuals with hyperbilirubinemia (Aono 1995, Chen 2014). The c.1099C>T; p.Arg367Cys variant is listed in the ClinVar database (Variation ID: 288098) and is found in the general population with an overall allele frequency of 0.002% (6/280,450 alleles) in the Genome Aggregation Database. The arginine at codon 367 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.268). Due to limited information, the clinical significance of the p.Arg367Cys variant is uncertain at this time. References: Aono S et al. Analysis of genes for bilirubin UDP-glucuronosyltransferase in Gilbert's syndrome. Lancet. 1995 Apr 15;345(8955):958-9. Chen Z et al. UGT1A1 sequence variants associated with risk of adult hyperbilirubinemia: a quantitative analysis. Gene. 2014 Nov 15;552(1):32-8. Minucci A et al. Identification of a novel mutation in UDP-glucuronosyltransferase (UGT1A1) gene in a child with neonatal unconjugated hyperbilirubinemia. Clin Biochem. 2013 Jan;46(1-2):170-2. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 03, 2021 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 367 of the UGT1A1 protein (p.Arg367Cys). This variant is present in population databases (rs55750087, gnomAD 0.006%). This missense change has been observed in individual(s) with Crigler-Najjar syndrome type II (PMID: 23099197). ClinVar contains an entry for this variant (Variation ID: 288098). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Crigler-Najjar syndrome type 1;C0017551:Gilbert syndrome;C0270210:Lucey-Driscoll syndrome;C1866173:Bilirubin, serum level of, quantitative trait locus 1;C2931132:Crigler-Najjar syndrome, type II Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 20, 2022 | - - |
UGT1A1-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 14, 2024 | The UGT1A1 c.1099C>T variant is predicted to result in the amino acid substitution p.Arg367Cys. This variant has been reported in the compound heterozygous state in an individual with neonatal unconjugated hyperbilirubinemia (Minucci et al. 2013. PubMed ID: 23099197). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;D;D;.;D;.;T;T;T;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
.;.;.;H;.;.;.;.;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Benign
Sift
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
D;D;.;D;D;.;D;.;D;D;D;D;.
Vest4
MVP
MPC
0.23, 0.38, 0.61, 0.60, 0.80, 0.23, 0.22, 0.64
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
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Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at