rs121908524
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000030.3(AGXT):c.454T>A(p.Phe152Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000107 in 1,597,214 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. F152C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000030.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AGXT | NM_000030.3 | c.454T>A | p.Phe152Ile | missense_variant | 4/11 | ENST00000307503.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGXT | ENST00000307503.4 | c.454T>A | p.Phe152Ile | missense_variant | 4/11 | 1 | NM_000030.3 | P1 | |
AGXT | ENST00000472436.1 | n.474T>A | non_coding_transcript_exon_variant | 4/5 | 2 | ||||
AGXT | ENST00000476698.1 | n.191T>A | non_coding_transcript_exon_variant | 1/4 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000145 AC: 22AN: 152114Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000899 AC: 20AN: 222532Hom.: 0 AF XY: 0.000133 AC XY: 16AN XY: 120332
GnomAD4 exome AF: 0.000103 AC: 149AN: 1445100Hom.: 0 Cov.: 31 AF XY: 0.0000962 AC XY: 69AN XY: 717328
GnomAD4 genome ? AF: 0.000145 AC: 22AN: 152114Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74292
ClinVar
Submissions by phenotype
Primary hyperoxaluria, type I Pathogenic:7Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 14, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | May 13, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 18, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 11, 2016 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | in vitro | Clinical Biochemistry Laboratory, Health Services Laboratory | Nov 27, 2014 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 25, 2013 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 14, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 152 of the AGXT protein (p.Phe152Ile). This variant is present in population databases (rs121908524, gnomAD 0.02%). This missense change has been observed in individual(s) with hyperoxaluria (PMID: 8101040, 11708860, 25363903). 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: 5645). 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: 10960483). For these reasons, this variant has been classified as Pathogenic. - |
Primary hyperoxaluria Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 02, 2018 | Variant summary: AGXT c.454T>A (p.Phe152Ile) results in a non-conservative amino acid change located in the Aminotransferase class V domain (IPR000192) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 248758 control chromosomes (gnomAD). The variant, c.454T>A, has been reported in the literature in multiple individuals affected with Primary Hyperoxaluria Type 1 (van der Hoeven_2012, Monico_2007). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "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