2-240871398-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The ENST00000307503.4(AGXT):c.473C>T(p.Ser158Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000829 in 1,448,276 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S158S) has been classified as Likely benign.
Frequency
Consequence
ENST00000307503.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AGXT | NM_000030.3 | c.473C>T | p.Ser158Leu | missense_variant | 4/11 | ENST00000307503.4 | NP_000021.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AGXT | ENST00000307503.4 | c.473C>T | p.Ser158Leu | missense_variant | 4/11 | 1 | NM_000030.3 | ENSP00000302620 | P1 | |
AGXT | ENST00000472436.1 | n.493C>T | non_coding_transcript_exon_variant | 4/5 | 2 | |||||
AGXT | ENST00000476698.1 | n.210C>T | non_coding_transcript_exon_variant | 1/4 | 5 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000441 AC: 1AN: 226530Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 122604
GnomAD4 exome AF: 0.00000829 AC: 12AN: 1448276Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 2AN XY: 719190
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Primary hyperoxaluria, type I Pathogenic:6
Likely pathogenic, criteria provided, single submitter | clinical testing | GenePathDx, GenePath diagnostics | Jul 07, 2017 | - - |
Pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Jan 17, 2019 | - - |
Pathogenic, no assertion criteria provided | in vitro | Clinical Biochemistry Laboratory, Health Services Laboratory | Nov 27, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 20, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 17, 2023 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 14, 2023 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 158 of the AGXT protein (p.Ser158Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with primary hyperoxaluria type 1 (PMID: 15849466, 17460142, 17495019, 23430879, 25629080, 30541997). 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: 204103). 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: 18782763, 22018727, 22923379). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 09, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30655312, 22923379, 15849466, 18782763, 22018727, 30541997) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at