rs146525143
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000030.3(AGXT):āc.822G>Cā(p.Glu274Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000030.3 missense
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 |
---|---|---|---|---|---|---|---|
AGXT | NM_000030.3 | c.822G>C | p.Glu274Asp | missense_variant | 8/11 | ENST00000307503.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGXT | ENST00000307503.4 | c.822G>C | p.Glu274Asp | missense_variant | 8/11 | 1 | NM_000030.3 | P1 | |
AGXT | ENST00000476698.1 | n.474G>C | non_coding_transcript_exon_variant | 4/4 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152204Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251322Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135872
GnomAD4 exome AF: 0.0000458 AC: 67AN: 1461870Hom.: 0 Cov.: 35 AF XY: 0.0000426 AC XY: 31AN XY: 727234
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152204Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2AN XY: 74342
ClinVar
Submissions by phenotype
Primary hyperoxaluria, type I Pathogenic:2Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 01, 2022 | - - |
Pathogenic, no assertion criteria provided | in vitro | Clinical Biochemistry Laboratory, Health Services Laboratory | Nov 27, 2014 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Rare Kidney Stone Consortium and the Mayo Clinic Hyperoxaluria Center, Mayo Clinic | Oct 27, 2023 | ACMG:PS3 PS5 PM2 PP1 PP3 PP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 22, 2018 | The AGXT c.822G>C (p.Glu274Asp) variant is a missense variant has been reported in a homozygous state in at least one individual with primary hyperoxaluria (Williams et al. 2009; Williams et al. 2015). The p.Glu274Asp variant is reported at a frequency of 0.000265 in the East Asian population of the Genome Aggregation Database. Functional studies in yeast and bacteria revealed that the p.Glu274Asp variant in the background of a well-known AGXT variant protein, had significantly reduced activity when compared to the wild type expressed in the same background (Lage et al. 2014). The evidence for this variant is limited. The p.Glu274Asp variant is classified as unknown significance but suspicious for pathogenicity for primary hyperoxaluria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 20, 2021 | NM_000030.2(AGXT):c.822G>C(E274D) is a missense variant classified as a variant of uncertain significance in the context of primary hyperoxaluria type 1. E274D has been observed in cases with relevant disease (PMID: 24988064). Functional assessments of this variant are available in the literature (PMID: 22923379, 24718375). E274D has been observed in population frequency databases (gnomAD: EAS 0.03%). In summary, there is insufficient evidence to classify NM_000030.2(AGXT):c.822G>C(E274D) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 19, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 274 of the AGXT protein (p.Glu274Asp). This variant is present in population databases (rs146525143, gnomAD 0.03%). This missense change has been observed in individual(s) with primary hyperoxaluria (PMID: 19479957, 25629080). ClinVar contains an entry for this variant (Variation ID: 204129). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AGXT protein function. Experimental studies have shown that this missense change affects AGXT function (PMID: 24718375). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at