rs121908523

Positions:

• chr2-240868986-G-A

Variant summary

Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Strong PP5_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:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: AGXT NM_000030.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 3.81

Genes affected

AGXT (HGNC:341): (alanine--glyoxylate aminotransferase) This gene is expressed only in the liver and the encoded protein is localized mostly in the peroxisomes, where it is involved in glyoxylate detoxification. Mutations in this gene, some of which alter subcellular targetting, have been associated with type I primary hyperoxaluria. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 26 ACMG points.

• PS1: Transcript NM_000030.3 (AGXT) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 2203295
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 2 uncertain in NM_000030.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-240868987-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 2-240868986-G-A is Pathogenic according to our data. Variant chr2-240868986-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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: 7 AN: 152174 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 247366 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134490

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000924 AC: 135 AN: 1460550 Hom.: 0 Cov.: 34 AF XY: 0.0000840 AC XY: 61 AN XY: 726570

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152174 Hom.: 0 Cov.: 34 AF XY: 0.0000404 AC XY: 3 AN XY: 74334

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000665 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type I Pathogenic:7 Other: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.75
Sift	Benign	0.053	T
Sift4G	Benign	0.090	T
Polyphen		1.0	D
Vest4		0.97
MutPred		0.94		Gain of MoRF binding (P = 0.0162);
MVP		0.92
MPC		0.26
ClinPred		0.96	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908523; hg19: chr2-241808403;