rs121908523
Variant summary
Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_StrongPM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000030.3(AGXT):c.121G>A(p.Gly41Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000088 in 1,612,724 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 Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G41E) has been classified as Pathogenic.
Frequency
Consequence
NM_000030.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 26 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AGXT | NM_000030.3 | c.121G>A | p.Gly41Arg | missense_variant | 1/11 | ENST00000307503.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGXT | ENST00000307503.4 | c.121G>A | p.Gly41Arg | missense_variant | 1/11 | 1 | NM_000030.3 | P1 | |
AGXT | ENST00000472436.1 | n.141G>A | non_coding_transcript_exon_variant | 1/5 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152174Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 247366Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134490
GnomAD4 exome AF: 0.0000924 AC: 135AN: 1460550Hom.: 0 Cov.: 34 AF XY: 0.0000840 AC XY: 61AN XY: 726570
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152174Hom.: 0 Cov.: 34 AF XY: 0.0000404 AC XY: 3AN XY: 74334
ClinVar
Submissions by phenotype
Primary hyperoxaluria, type I Pathogenic:7Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 20, 2021 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 04, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 27, 2021 | - - |
Pathogenic, no assertion criteria provided | in vitro | Clinical Biochemistry Laboratory, Health Services Laboratory | Nov 27, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 20, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 25, 2013 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 10, 2023 | Published functional studies demonstrated impaired enzyme activity (Coulter-Mackie et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34758253, 21176891, 10960483, 26161999, 2889341, 32518881, 8101040, 23229545, 20133649, 23597595, 22923379, 15802217) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 20, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 41 of the AGXT protein (p.Gly41Arg). This variant is present in population databases (rs121908523, gnomAD 0.003%). This missense change has been observed in individual(s) with primary hyperoxaluria type 1 (PMID: 8101040). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5644). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects AGXT function (PMID: 15802217, 20133649, 23229545). For these reasons, this variant has been classified as Pathogenic. - |
Nephrocalcinosis;C0392525:Nephrolithiasis Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Sep 08, 2017 | - - |
Primary hyperoxaluria Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 16, 2022 | Variant summary: AGXT c.121G>A (p.Gly41Arg) results in a non-conservative amino acid change located in the Aminotransferase class V domain (IPR000192) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 247366 control chromosomes. c.121G>A has been reported in the literature as bialleic homozygous or compound heterozygous genotypes in multiple individuals affected with Primary Hyperoxaluria Type 1 or 2 (example, Monico_2007, Birtel_2019, Frishberg_2005). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Coulter-Mackie_2005). The most pronounced variant effect results in aggregation of AGT and <2% of normal Alanine:glyoxylate aminotransferase-1 (AGT) enzyme activity. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at