chr2-233772281-C-T
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_007120.3(UGT1A4):c.1327C>T(p.Arg443Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,614,084 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 1 hom. )
Consequence
UGT1A4
NM_007120.3 missense
NM_007120.3 missense
Scores
7
7
5
Clinical Significance
Conservation
PhyloP100: 3.03
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 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| UGT1A4 | NM_007120.3 | c.1327C>T | p.Arg443Cys | missense_variant | Exon 5 of 5 | ENST00000373409.8 | NP_009051.1 | |
| UGT1A5 | NM_019078.2 | c.1327C>T | p.Arg443Cys | missense_variant | Exon 5 of 5 | ENST00000373414.4 | NP_061951.1 | |
| UGT1A3 | NM_019093.4 | c.1327C>T | p.Arg443Cys | missense_variant | Exon 5 of 5 | ENST00000482026.6 | NP_061966.1 | |
| UGT1A1 | NM_000463.3 | c.1324C>T | p.Arg442Cys | missense_variant | Exon 5 of 5 | ENST00000305208.10 | NP_000454.1 | |
| UGT1A6 | NM_001072.4 | c.1321C>T | p.Arg441Cys | missense_variant | Exon 5 of 5 | ENST00000305139.11 | NP_001063.2 | |
| UGT1A10 | NM_019075.4 | c.1315C>T | p.Arg439Cys | missense_variant | Exon 5 of 5 | ENST00000344644.10 | NP_061948.1 | |
| UGT1A8 | NM_019076.5 | c.1315C>T | p.Arg439Cys | missense_variant | Exon 5 of 5 | ENST00000373450.5 | NP_061949.3 | |
| UGT1A7 | NM_019077.3 | c.1315C>T | p.Arg439Cys | missense_variant | Exon 5 of 5 | ENST00000373426.4 | NP_061950.2 | |
| UGT1A9 | NM_021027.3 | c.1315C>T | p.Arg439Cys | missense_variant | Exon 5 of 5 | ENST00000354728.5 | NP_066307.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| UGT1A4 | ENST00000373409.8 | c.1327C>T | p.Arg443Cys | missense_variant | Exon 5 of 5 | 1 | NM_007120.3 | ENSP00000362508.4 | ||
| UGT1A5 | ENST00000373414.4 | c.1327C>T | p.Arg443Cys | missense_variant | Exon 5 of 5 | 1 | NM_019078.2 | ENSP00000362513.3 | ||
| UGT1A3 | ENST00000482026.6 | c.1327C>T | p.Arg443Cys | missense_variant | Exon 5 of 5 | 1 | NM_019093.4 | ENSP00000418532.1 | ||
| UGT1A1 | ENST00000305208.10 | c.1324C>T | p.Arg442Cys | missense_variant | Exon 5 of 5 | 1 | NM_000463.3 | ENSP00000304845.5 | ||
| UGT1A6 | ENST00000305139.11 | c.1321C>T | p.Arg441Cys | missense_variant | Exon 5 of 5 | 1 | NM_001072.4 | ENSP00000303174.6 | ||
| UGT1A10 | ENST00000344644.10 | c.1315C>T | p.Arg439Cys | missense_variant | Exon 5 of 5 | 1 | NM_019075.4 | ENSP00000343838.5 | ||
| UGT1A9 | ENST00000354728.5 | c.1315C>T | p.Arg439Cys | missense_variant | Exon 5 of 5 | 1 | NM_021027.3 | ENSP00000346768.4 | ||
| UGT1A7 | ENST00000373426.4 | c.1315C>T | p.Arg439Cys | missense_variant | Exon 5 of 5 | 1 | NM_019077.3 | ENSP00000362525.3 | ||
| UGT1A8 | ENST00000373450.5 | c.1315C>T | p.Arg439Cys | missense_variant | Exon 5 of 5 | 1 | NM_019076.5 | ENSP00000362549.4 |
Frequencies
GnomAD3 genomes 0.0000854 AC: 13AN: 152204Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000521 AC: 13AN: 249424Hom.: 0 AF XY: 0.0000592 AC XY: 8AN XY: 135040
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GnomAD4 exome AF: 0.000135 AC: 197AN: 1461880Hom.: 1 Cov.: 33 AF XY: 0.000122 AC XY: 89AN XY: 727236
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GnomAD4 genome 0.0000854 AC: 13AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74360
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:5
Apr 20, 2022
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Sep 17, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 442 of the UGT1A1 protein (p.Arg442Cys). This variant is present in population databases (rs143033456, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with UGT1A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 286999). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt UGT1A1 protein function with a positive predictive value of 80%. 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. -
Apr 19, 2016
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Feb 13, 2017
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The R442C variant in the UGT1A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R442C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R442C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret R442C as a variant of uncertain significance. -
Dec 23, 2022
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Crigler-Najjar syndrome Uncertain:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
UGT1A1-related disorder Uncertain:1
Jul 25, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing
The UGT1A1 c.1324C>T variant is predicted to result in the amino acid substitution p.Arg442Cys. To our knowledge, this variant has not been reported in the literature in individuals affected with UGT1A1-related conditions. This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. 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
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;D;D;D;.;D;D;D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
.;.;H;.;.;.;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D;D
Polyphen
D;D;D;D;.;D;D;D;D;D
Vest4
MVP
MPC
0.19, 0.35, 0.56, 0.52, 0.74, 0.19, 0.19, 0.64
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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