chr2-233772281-C-T
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
Consequence
NM_007120.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
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 AF: 0.0000854 AC: 13AN: 152204Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000521 AC: 13AN: 249424Hom.: 0 AF XY: 0.0000592 AC XY: 8AN XY: 135040
GnomAD4 exome AF: 0.000135 AC: 197AN: 1461880Hom.: 1 Cov.: 33 AF XY: 0.000122 AC XY: 89AN XY: 727236
GnomAD4 genome AF: 0.0000854 AC: 13AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74360
ClinVar
Submissions by phenotype
not provided Uncertain:5
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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. -
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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. -
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Crigler-Najjar syndrome Uncertain:1
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
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UGT1A1-related disorder Uncertain:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at