2-233760908-G-GCAGC
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000463.3(UGT1A1):c.622_625dupCAGC(p.Arg209ProfsTer50) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
UGT1A1
NM_000463.3 frameshift
NM_000463.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.69
Publications
2 publications found
Genes affected
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]
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]
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: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-233760908-G-GCAGC is Pathogenic according to our data. Variant chr2-233760908-G-GCAGC is described in ClinVar as Pathogenic. ClinVar VariationId is 437209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| UGT1A1 | NM_000463.3 | c.622_625dupCAGC | p.Arg209ProfsTer50 | frameshift_variant | Exon 1 of 5 | ENST00000305208.10 | NP_000454.1 | |
| UGT1A4 | NM_007120.3 | c.868-6125_868-6122dupCAGC | intron_variant | Intron 1 of 4 | ENST00000373409.8 | NP_009051.1 | ||
| UGT1A5 | NM_019078.2 | c.868-6125_868-6122dupCAGC | intron_variant | Intron 1 of 4 | ENST00000373414.4 | NP_061951.1 | ||
| UGT1A3 | NM_019093.4 | c.868-6125_868-6122dupCAGC | intron_variant | Intron 1 of 4 | ENST00000482026.6 | NP_061966.1 | ||
| UGT1A6 | NM_001072.4 | c.862-6125_862-6122dupCAGC | intron_variant | Intron 1 of 4 | ENST00000305139.11 | NP_001063.2 | ||
| UGT1A10 | NM_019075.4 | c.856-6125_856-6122dupCAGC | intron_variant | Intron 1 of 4 | ENST00000344644.10 | NP_061948.1 | ||
| UGT1A8 | NM_019076.5 | c.856-6125_856-6122dupCAGC | intron_variant | Intron 1 of 4 | ENST00000373450.5 | NP_061949.3 | ||
| UGT1A7 | NM_019077.3 | c.856-6125_856-6122dupCAGC | intron_variant | Intron 1 of 4 | ENST00000373426.4 | NP_061950.2 | ||
| UGT1A9 | NM_021027.3 | c.856-6125_856-6122dupCAGC | intron_variant | Intron 1 of 4 | ENST00000354728.5 | NP_066307.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| UGT1A1 | ENST00000305208.10 | c.622_625dupCAGC | p.Arg209ProfsTer50 | frameshift_variant | Exon 1 of 5 | 1 | NM_000463.3 | ENSP00000304845.5 | ||
| UGT1A4 | ENST00000373409.8 | c.868-6125_868-6122dupCAGC | intron_variant | Intron 1 of 4 | 1 | NM_007120.3 | ENSP00000362508.4 | |||
| UGT1A5 | ENST00000373414.4 | c.868-6125_868-6122dupCAGC | intron_variant | Intron 1 of 4 | 1 | NM_019078.2 | ENSP00000362513.3 | |||
| UGT1A3 | ENST00000482026.6 | c.868-6125_868-6122dupCAGC | intron_variant | Intron 1 of 4 | 1 | NM_019093.4 | ENSP00000418532.1 | |||
| UGT1A6 | ENST00000305139.11 | c.862-6125_862-6122dupCAGC | intron_variant | Intron 1 of 4 | 1 | NM_001072.4 | ENSP00000303174.6 | |||
| UGT1A10 | ENST00000344644.10 | c.856-6125_856-6122dupCAGC | intron_variant | Intron 1 of 4 | 1 | NM_019075.4 | ENSP00000343838.5 | |||
| UGT1A9 | ENST00000354728.5 | c.856-6125_856-6122dupCAGC | intron_variant | Intron 1 of 4 | 1 | NM_021027.3 | ENSP00000346768.4 | |||
| UGT1A7 | ENST00000373426.4 | c.856-6125_856-6122dupCAGC | intron_variant | Intron 1 of 4 | 1 | NM_019077.3 | ENSP00000362525.3 | |||
| UGT1A8 | ENST00000373450.5 | c.856-6125_856-6122dupCAGC | intron_variant | Intron 1 of 4 | 1 | NM_019076.5 | ENSP00000362549.4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD2 exomes AF: 0.0000119 AC: 3AN: 251486 AF XY: 0.0000221 show subpopulations
GnomAD2 exomes
AF:
AC:
3
AN:
251486
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
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Gnomad ASJ exome
AF:
Gnomad EAS exome
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Gnomad FIN exome
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Gnomad NFE exome
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Gnomad OTH exome
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461884Hom.: 0 Cov.: 34 AF XY: 0.00000963 AC XY: 7AN XY: 727244 show subpopulations
GnomAD4 exome
AF:
AC:
8
AN:
1461884
Hom.:
Cov.:
34
AF XY:
AC XY:
7
AN XY:
727244
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33480
American (AMR)
AF:
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
0
AN:
39700
South Asian (SAS)
AF:
AC:
8
AN:
86258
European-Finnish (FIN)
AF:
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1112008
Other (OTH)
AF:
AC:
0
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.519
Heterozygous variant carriers
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2
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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30-35
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GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Feb 01, 2017
Eurofins Ntd Llc (ga)
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Mar 18, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change creates a premature translational stop signal (p.Arg209Profs*50) in the UGT1A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in UGT1A1 are known to be pathogenic (PMID: 23290513). This variant is present in population databases (rs766536479, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Crigler-Najjar syndrome type I (PMID: 31145902). ClinVar contains an entry for this variant (Variation ID: 437209). For these reasons, this variant has been classified as Pathogenic. -
Crigler-Najjar syndrome Pathogenic:1
May 30, 2017
Genetic Services Laboratory, University of Chicago
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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