2-233772524-C-T
Variant names:
Variant summary
Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_007120.3(UGT1A4):c.1570C>T(p.Arg524*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,613,838 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R524R) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000022 ( 0 hom. )
Consequence
UGT1A4
NM_007120.3 stop_gained
NM_007120.3 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: 0.207
Publications
5 publications found
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]
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 4 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0218 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
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.1570C>T | p.Arg524* | stop_gained | Exon 5 of 5 | ENST00000373409.8 | NP_009051.1 | |
| UGT1A5 | NM_019078.2 | c.1570C>T | p.Arg524* | stop_gained | Exon 5 of 5 | ENST00000373414.4 | NP_061951.1 | |
| UGT1A3 | NM_019093.4 | c.1570C>T | p.Arg524* | stop_gained | Exon 5 of 5 | ENST00000482026.6 | NP_061966.1 | |
| UGT1A1 | NM_000463.3 | c.1567C>T | p.Arg523* | stop_gained | Exon 5 of 5 | ENST00000305208.10 | NP_000454.1 | |
| UGT1A6 | NM_001072.4 | c.1564C>T | p.Arg522* | stop_gained | Exon 5 of 5 | ENST00000305139.11 | NP_001063.2 | |
| UGT1A10 | NM_019075.4 | c.1558C>T | p.Arg520* | stop_gained | Exon 5 of 5 | ENST00000344644.10 | NP_061948.1 | |
| UGT1A8 | NM_019076.5 | c.1558C>T | p.Arg520* | stop_gained | Exon 5 of 5 | ENST00000373450.5 | NP_061949.3 | |
| UGT1A7 | NM_019077.3 | c.1558C>T | p.Arg520* | stop_gained | Exon 5 of 5 | ENST00000373426.4 | NP_061950.2 | |
| UGT1A9 | NM_021027.3 | c.1558C>T | p.Arg520* | stop_gained | 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.1570C>T | p.Arg524* | stop_gained | Exon 5 of 5 | 1 | NM_007120.3 | ENSP00000362508.4 | ||
| UGT1A5 | ENST00000373414.4 | c.1570C>T | p.Arg524* | stop_gained | Exon 5 of 5 | 1 | NM_019078.2 | ENSP00000362513.3 | ||
| UGT1A3 | ENST00000482026.6 | c.1570C>T | p.Arg524* | stop_gained | Exon 5 of 5 | 1 | NM_019093.4 | ENSP00000418532.1 | ||
| UGT1A1 | ENST00000305208.10 | c.1567C>T | p.Arg523* | stop_gained | Exon 5 of 5 | 1 | NM_000463.3 | ENSP00000304845.5 | ||
| UGT1A6 | ENST00000305139.11 | c.1564C>T | p.Arg522* | stop_gained | Exon 5 of 5 | 1 | NM_001072.4 | ENSP00000303174.6 | ||
| UGT1A10 | ENST00000344644.10 | c.1558C>T | p.Arg520* | stop_gained | Exon 5 of 5 | 1 | NM_019075.4 | ENSP00000343838.5 | ||
| UGT1A9 | ENST00000354728.5 | c.1558C>T | p.Arg520* | stop_gained | Exon 5 of 5 | 1 | NM_021027.3 | ENSP00000346768.4 | ||
| UGT1A7 | ENST00000373426.4 | c.1558C>T | p.Arg520* | stop_gained | Exon 5 of 5 | 1 | NM_019077.3 | ENSP00000362525.3 | ||
| UGT1A8 | ENST00000373450.5 | c.1558C>T | p.Arg520* | stop_gained | Exon 5 of 5 | 1 | NM_019076.5 | ENSP00000362549.4 |
Frequencies
GnomAD3 genomes 0.00000658 AC: 1AN: 151952Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
151952
Hom.:
Cov.:
32
Gnomad AFR
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GnomAD2 exomes AF: 0.0000161 AC: 4AN: 249194 AF XY: 0.00000741 show subpopulations
GnomAD2 exomes
AF:
AC:
4
AN:
249194
AF XY:
Gnomad AFR exome
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GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461886Hom.: 0 Cov.: 33 AF XY: 0.0000206 AC XY: 15AN XY: 727242 show subpopulations
GnomAD4 exome
AF:
AC:
32
AN:
1461886
Hom.:
Cov.:
33
AF XY:
AC XY:
15
AN XY:
727242
show subpopulations
African (AFR)
AF:
AC:
2
AN:
33480
American (AMR)
AF:
AC:
1
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
2
AN:
39700
South Asian (SAS)
AF:
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
AC:
1
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
24
AN:
1112004
Other (OTH)
AF:
AC:
2
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
2
4
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11
0.00
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Allele balance
Age Distribution
Exome Het
Variant carriers
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GnomAD4 genome 0.00000658 AC: 1AN: 151952Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74210 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome
AF:
AC:
1
AN:
151952
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74210
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
41352
American (AMR)
AF:
AC:
0
AN:
15268
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3468
East Asian (EAS)
AF:
AC:
0
AN:
5186
South Asian (SAS)
AF:
AC:
0
AN:
4808
European-Finnish (FIN)
AF:
AC:
0
AN:
10560
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
1
AN:
68002
Other (OTH)
AF:
AC:
0
AN:
2080
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
AF:
AC:
1
EpiCase
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EpiControl
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:2Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
- -
Jul 25, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The UGT1A1 c.1567C>T; p.Arg523Ter variant (rs770564267, ClinVar Variation ID: 548505) is reported in the literature in a newborn male with Crigler-Najjar type II along with co-inheritance of G6PD and PK deficiencies (Minucci 2015). The p.Arg523Ter variant is observed in the general population with an overall allele frequency of 0.002% (4/249194 alleles) in the Genome Aggregation Database (v2.1.1). This variant results in a premature termination codon in the last exon of the UGT1A1 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated UGT1A1 protein. Due to limited information, the clinical significance of this variant is uncertain at this time. References: Minucci A et al. Co-inheritance of G6PD and PK deficiencies in a neonate carrying a Novel UGT1A1 genotype associated to Crigler-Najjar type II syndrome. Pediatr Blood Cancer. 2015 Sep;62(9):1680-1. PMID: 25822733. -
-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
- -
Crigler-Najjar syndrome Uncertain:1
Dec 24, 2022
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Crigler-Najjar syndrome, type II Uncertain:1
Feb 23, 2023
3billion
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. The variant has been reported to be associated with UGT1A1 related disorder (ClinVar ID: VCV000548505 / PMID: 25822733). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
PhyloP100
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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