chr2-240874035-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000030.3(AGXT):c.653C>T(p.Ser218Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,612 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 (★★).
Frequency
Consequence
NM_000030.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152224Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251102Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135766
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461388Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726998
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152224Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74360
ClinVar
Submissions by phenotype
Primary hyperoxaluria, type I Pathogenic:4
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The AGXT c.653C>T (p.Ser218Leu) variant has been observed to be homozygous in individuals affected with primary hyperoxaluria type I (Coulter-Mackie MB et al., 2005). This variant has been reported to affect AGXT protein function (Oppici E et al., 2011). This variant has allele frequency of 0.001% in the gnomad and novel in 1000 genome database. This variant has been submitted to ClinVar as Pathogenic. The amino acid Ser at position 218 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ser218Leu in AGXT is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:2
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects AGXT function (PMID: 22018727). 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. ClinVar contains an entry for this variant (Variation ID: 188979). This missense change has been observed in individual(s) with primary hyperoxaluria type I (PMID: 15963748). This variant is present in population databases (rs180177253, gnomAD 0.01%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 218 of the AGXT protein (p.Ser218Leu). -
PS3, PS4_moderate, PM2, PP1, PP4 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at