chr2-233760364-ATGCTGGGAAGATAC-A
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000463.3(UGT1A1):c.80_93delCTGGGAAGATACTG(p.Ala27ValfsTer25) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
UGT1A1
NM_000463.3 frameshift
NM_000463.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.53
Publications
0 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]
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 16 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 73 pathogenic variants in the truncated region.
PP5
Variant 2-233760364-ATGCTGGGAAGATAC-A is Pathogenic according to our data. Variant chr2-233760364-ATGCTGGGAAGATAC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1325329.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.80_93delCTGGGAAGATACTG | p.Ala27ValfsTer25 | frameshift_variant | Exon 1 of 5 | ENST00000305208.10 | NP_000454.1 | |
| UGT1A4 | NM_007120.3 | c.868-6667_868-6654delCTGGGAAGATACTG | intron_variant | Intron 1 of 4 | ENST00000373409.8 | NP_009051.1 | ||
| UGT1A5 | NM_019078.2 | c.868-6667_868-6654delCTGGGAAGATACTG | intron_variant | Intron 1 of 4 | ENST00000373414.4 | NP_061951.1 | ||
| UGT1A3 | NM_019093.4 | c.868-6667_868-6654delCTGGGAAGATACTG | intron_variant | Intron 1 of 4 | ENST00000482026.6 | NP_061966.1 | ||
| UGT1A6 | NM_001072.4 | c.862-6667_862-6654delCTGGGAAGATACTG | intron_variant | Intron 1 of 4 | ENST00000305139.11 | NP_001063.2 | ||
| UGT1A10 | NM_019075.4 | c.856-6667_856-6654delCTGGGAAGATACTG | intron_variant | Intron 1 of 4 | ENST00000344644.10 | NP_061948.1 | ||
| UGT1A8 | NM_019076.5 | c.856-6667_856-6654delCTGGGAAGATACTG | intron_variant | Intron 1 of 4 | ENST00000373450.5 | NP_061949.3 | ||
| UGT1A7 | NM_019077.3 | c.856-6667_856-6654delCTGGGAAGATACTG | intron_variant | Intron 1 of 4 | ENST00000373426.4 | NP_061950.2 | ||
| UGT1A9 | NM_021027.3 | c.856-6667_856-6654delCTGGGAAGATACTG | 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.80_93delCTGGGAAGATACTG | p.Ala27ValfsTer25 | frameshift_variant | Exon 1 of 5 | 1 | NM_000463.3 | ENSP00000304845.5 | ||
| UGT1A4 | ENST00000373409.8 | c.868-6667_868-6654delCTGGGAAGATACTG | intron_variant | Intron 1 of 4 | 1 | NM_007120.3 | ENSP00000362508.4 | |||
| UGT1A5 | ENST00000373414.4 | c.868-6667_868-6654delCTGGGAAGATACTG | intron_variant | Intron 1 of 4 | 1 | NM_019078.2 | ENSP00000362513.3 | |||
| UGT1A3 | ENST00000482026.6 | c.868-6667_868-6654delCTGGGAAGATACTG | intron_variant | Intron 1 of 4 | 1 | NM_019093.4 | ENSP00000418532.1 | |||
| UGT1A6 | ENST00000305139.11 | c.862-6667_862-6654delCTGGGAAGATACTG | intron_variant | Intron 1 of 4 | 1 | NM_001072.4 | ENSP00000303174.6 | |||
| UGT1A10 | ENST00000344644.10 | c.856-6667_856-6654delCTGGGAAGATACTG | intron_variant | Intron 1 of 4 | 1 | NM_019075.4 | ENSP00000343838.5 | |||
| UGT1A9 | ENST00000354728.5 | c.856-6667_856-6654delCTGGGAAGATACTG | intron_variant | Intron 1 of 4 | 1 | NM_021027.3 | ENSP00000346768.4 | |||
| UGT1A7 | ENST00000373426.4 | c.856-6667_856-6654delCTGGGAAGATACTG | intron_variant | Intron 1 of 4 | 1 | NM_019077.3 | ENSP00000362525.3 | |||
| UGT1A8 | ENST00000373450.5 | c.856-6667_856-6654delCTGGGAAGATACTG | intron_variant | Intron 1 of 4 | 1 | NM_019076.5 | ENSP00000362549.4 |
Frequencies
GnomAD3 genomes 0.0000460 AC: 7AN: 152240Hom.: 0 Cov.: 33 show subpopulations
GnomAD3 genomes
AF:
AC:
7
AN:
152240
Hom.:
Cov.:
33
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GnomAD2 exomes AF: 0.0000119 AC: 3AN: 251070 AF XY: 0.00000737 show subpopulations
GnomAD2 exomes
AF:
AC:
3
AN:
251070
AF XY:
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461796Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 727198 show subpopulations
GnomAD4 exome
AF:
AC:
6
AN:
1461796
Hom.:
AF XY:
AC XY:
3
AN XY:
727198
show subpopulations
African (AFR)
AF:
AC:
6
AN:
33478
American (AMR)
AF:
AC:
0
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
0
AN:
39698
South Asian (SAS)
AF:
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
AC:
0
AN:
53410
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111956
Other (OTH)
AF:
AC:
0
AN:
60380
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
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0.95
Allele balance
GnomAD4 genome 0.0000460 AC: 7AN: 152240Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74378 show subpopulations
GnomAD4 genome
AF:
AC:
7
AN:
152240
Hom.:
Cov.:
33
AF XY:
AC XY:
5
AN XY:
74378
show subpopulations
African (AFR)
AF:
AC:
6
AN:
41470
American (AMR)
AF:
AC:
1
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5194
South Asian (SAS)
AF:
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
0
AN:
68040
Other (OTH)
AF:
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
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Bravo
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Mar 30, 2023
Revvity Omics, Revvity
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Nov 10, 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.Ala27Valfs*25) 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 (rs775463336, gnomAD 0.02%). 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: 1325329). For these reasons, this variant has been classified as Pathogenic. -
UGT1A1-related disorder Pathogenic:1
Aug 14, 2024
PreventionGenetics, part of Exact Sciences
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
The UGT1A1 c.80_93del14 variant is predicted to result in a frameshift and premature protein termination (p.Ala27Valfs*25). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD. Frameshift variants in UGT1A1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -
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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