rs748219743
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000463.3(UGT1A1):c.353dupA(p.Asp119fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
UGT1A1
NM_000463.3 frameshift
NM_000463.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -1.38
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 made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 2-233760634-T-TA is Pathogenic according to our data. Variant chr2-233760634-T-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 266037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
UGT1A1 | NM_000463.3 | c.353dupA | p.Asp119fs | frameshift_variant | 1/5 | ENST00000305208.10 | NP_000454.1 | |
UGT1A4 | NM_007120.3 | c.868-6394dupA | intron_variant | ENST00000373409.8 | NP_009051.1 | |||
UGT1A5 | NM_019078.2 | c.868-6394dupA | intron_variant | ENST00000373414.4 | NP_061951.1 | |||
UGT1A3 | NM_019093.4 | c.868-6394dupA | intron_variant | ENST00000482026.6 | NP_061966.1 | |||
UGT1A6 | NM_001072.4 | c.862-6394dupA | intron_variant | ENST00000305139.11 | NP_001063.2 | |||
UGT1A10 | NM_019075.4 | c.856-6394dupA | intron_variant | ENST00000344644.10 | NP_061948.1 | |||
UGT1A8 | NM_019076.5 | c.856-6394dupA | intron_variant | ENST00000373450.5 | NP_061949.3 | |||
UGT1A7 | NM_019077.3 | c.856-6394dupA | intron_variant | ENST00000373426.4 | NP_061950.2 | |||
UGT1A9 | NM_021027.3 | c.856-6394dupA | intron_variant | ENST00000354728.5 | NP_066307.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
UGT1A1 | ENST00000305208.10 | c.353dupA | p.Asp119fs | frameshift_variant | 1/5 | 1 | NM_000463.3 | ENSP00000304845.5 | ||
UGT1A4 | ENST00000373409.8 | c.868-6394dupA | intron_variant | 1 | NM_007120.3 | ENSP00000362508.4 | ||||
UGT1A5 | ENST00000373414.4 | c.868-6394dupA | intron_variant | 1 | NM_019078.2 | ENSP00000362513.3 | ||||
UGT1A3 | ENST00000482026.6 | c.868-6394dupA | intron_variant | 1 | NM_019093.4 | ENSP00000418532.1 | ||||
UGT1A6 | ENST00000305139.11 | c.862-6394dupA | intron_variant | 1 | NM_001072.4 | ENSP00000303174.6 | ||||
UGT1A10 | ENST00000344644.10 | c.856-6394dupA | intron_variant | 1 | NM_019075.4 | ENSP00000343838.5 | ||||
UGT1A9 | ENST00000354728.5 | c.856-6394dupA | intron_variant | 1 | NM_021027.3 | ENSP00000346768.4 | ||||
UGT1A7 | ENST00000373426.4 | c.856-6394dupA | intron_variant | 1 | NM_019077.3 | ENSP00000362525.3 | ||||
UGT1A8 | ENST00000373450.5 | c.856-6394dupA | intron_variant | 1 | NM_019076.5 | ENSP00000362549.4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251296Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135864
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461884Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8AN XY: 727238
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GnomAD4 genome Cov.: 33
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Crigler-Najjar syndrome type 1 Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Feb 26, 2019 | The observed variant NM_000463.2:c.353dupA/p.D119G fs*28 in exon 1 of the UTG1A1 gene has not been reported in the 1000 Genomes and ExAC databases. The in silico prediction of this variant is disease causing by MutationTaster2. The proband, born of a non-consanguineous marriage presented with neonatal jaundice. Molecular studies revealed her to be homozygous for the above mentioned variant. Her younger brother also presented with a similar phenotype. Molecular analysis was carried out for brother and both parents for the presence of the aforementioned variant. The brother was homozygous for the same variant as observed in the proband. The parents were both found to be carriers for the same variant. Since both the children were affected and had homozygous mutant genotype as compared to the heterozygous mutant parents, this suggests that the variant is pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | May 20, 2023 | The observed frameshift variant c.353dup (p.Asp119GlyfsTer28) in UGT1A1 gene has been submitted to the ClinVar database as Pathogenic (multiple submissions). The p.Asp119GlyfsTer28 variant is present with an allele frequency of 0.0008% in gnomAD exomes database. This variant causes a frameshift starting with codon Aspartic Acid 119, changes this amino acid to Glycine residue, and creates a premature Stop codon at position 28 of the new reading frame, denoted p.Asp119GlyfsTer28. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. Multiple downstream frameshift variants on exon 1 have previously been reported to be pathogenic. For these reasons, this variant has been classified as Pathogenic. - |
Gilbert syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 16, 2016 | - - |
UGT1A1-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 07, 2023 | The UGT1A1 c.353dupA variant is predicted to result in a frameshift and premature protein termination (p.Asp119Glyfs*28). This variant has been reported in the homozygous state in a patient with type I Crigler-Najjar syndrome (Wang et al. 2011. PubMed ID: 22340355). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in UGT1A1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 25, 2023 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
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