rs755218546
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5
The NM_007120.3(UGT1A4):c.1087G>A(p.Gly363Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G363V) has been classified as Uncertain significance.
Frequency
Consequence
NM_007120.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UGT1A4 | NM_007120.3 | c.1087G>A | p.Gly363Ser | missense_variant, splice_region_variant | 3/5 | ENST00000373409.8 | |
UGT1A5 | NM_019078.2 | c.1087G>A | p.Gly363Ser | missense_variant, splice_region_variant | 3/5 | ENST00000373414.4 | |
UGT1A3 | NM_019093.4 | c.1087G>A | p.Gly363Ser | missense_variant, splice_region_variant | 3/5 | ENST00000482026.6 | |
UGT1A1 | NM_000463.3 | c.1084G>A | p.Gly362Ser | missense_variant, splice_region_variant | 3/5 | ENST00000305208.10 | |
UGT1A6 | NM_001072.4 | c.1081G>A | p.Gly361Ser | missense_variant, splice_region_variant | 3/5 | ENST00000305139.11 | |
UGT1A10 | NM_019075.4 | c.1075G>A | p.Gly359Ser | missense_variant, splice_region_variant | 3/5 | ENST00000344644.10 | |
UGT1A8 | NM_019076.5 | c.1075G>A | p.Gly359Ser | missense_variant, splice_region_variant | 3/5 | ENST00000373450.5 | |
UGT1A7 | NM_019077.3 | c.1075G>A | p.Gly359Ser | missense_variant, splice_region_variant | 3/5 | ENST00000373426.4 | |
UGT1A9 | NM_021027.3 | c.1075G>A | p.Gly359Ser | missense_variant, splice_region_variant | 3/5 | ENST00000354728.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UGT1A4 | ENST00000373409.8 | c.1087G>A | p.Gly363Ser | missense_variant, splice_region_variant | 3/5 | 1 | NM_007120.3 | P1 | |
UGT1A5 | ENST00000373414.4 | c.1087G>A | p.Gly363Ser | missense_variant, splice_region_variant | 3/5 | 1 | NM_019078.2 | P1 | |
UGT1A3 | ENST00000482026.6 | c.1087G>A | p.Gly363Ser | missense_variant, splice_region_variant | 3/5 | 1 | NM_019093.4 | P1 | |
UGT1A1 | ENST00000305208.10 | c.1084G>A | p.Gly362Ser | missense_variant, splice_region_variant | 3/5 | 1 | NM_000463.3 | P1 | |
UGT1A6 | ENST00000305139.11 | c.1081G>A | p.Gly361Ser | missense_variant, splice_region_variant | 3/5 | 1 | NM_001072.4 | P1 | |
UGT1A10 | ENST00000344644.10 | c.1075G>A | p.Gly359Ser | missense_variant, splice_region_variant | 3/5 | 1 | NM_019075.4 | P1 | |
UGT1A9 | ENST00000354728.5 | c.1075G>A | p.Gly359Ser | missense_variant, splice_region_variant | 3/5 | 1 | NM_021027.3 | P1 | |
UGT1A7 | ENST00000373426.4 | c.1075G>A | p.Gly359Ser | missense_variant, splice_region_variant | 3/5 | 1 | NM_019077.3 | P1 | |
UGT1A8 | ENST00000373450.5 | c.1075G>A | p.Gly359Ser | missense_variant, splice_region_variant | 3/5 | 1 | NM_019076.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152158Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000402 AC: 10AN: 249058Hom.: 0 AF XY: 0.0000519 AC XY: 7AN XY: 134822
GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461894Hom.: 0 Cov.: 36 AF XY: 0.0000358 AC XY: 26AN XY: 727248
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152158Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74328
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 21, 2017 | The c.1084 G>A variant in the UGT1A1 gene has been reported previously in the homozygous state and in the heterozygous state with a second variant in the promotor region in patients with unconjugated hyperbilirubinemia (Aggarwal et al., 2010; Gupta et al., 2015). The c.1084 G>A 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). In vitro studies of this variant using a pCAS2 splicing minigene reporter assay indicate that the c.1084 G>A variant abolishes the natural splice donor site, leading to the creation of a cryptic splice site and a frameshift deletion of 31 nucleotides from the 3-prime end of exon 3, which forms a premature stop codon at position 3 of the new reading frame (Gupta et al., 2015). If c.1084 G>A does not alter splicing, it will result in the G362S missense change. The G362S 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. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret c.1084 G>A as a pathogenic variant. - |
UGT1A1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 14, 2023 | The UGT1A1 c.1084G>A variant is predicted to result in the amino acid substitution p.Gly362Ser. This variant has been reported in the homozygous state in an individual with Crigler-Najjar syndrome and in the heterozygous state in individuals with unconjugated hyperbilirubinemia (Gupta et al. 2015. PubMed ID: 26716871; Aggarwal et al. 2009. PubMed ID: 19953640; Mi et al. 2019. PubMed ID: 31467903). This variant is located within the last base of exon 3 and is predicted to alter splicing based on available splicing prediction programs (Alamut Visual Plus v1.6.1). In addition, a functional study showed that this variant impacts splicing (Figure 4, Gupta et al. 2015. PubMed ID: 26716871). This variant is reported in 0.033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-234676582-G-A). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at