chr2-240877555-C-T

Position:

• chr2-240877555-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000030.3(AGXT):​c.865C>T​(p.Arg289Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000452 in 1,549,706 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: AGXT NM_000030.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: -0.0110

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGXT	NM_000030.3	c.865C>T	p.Arg289Cys	missense_variant	9/11	ENST00000307503.4	NP_000021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4	c.865C>T	p.Arg289Cys	missense_variant	9/11	1	NM_000030.3	ENSP00000302620	P1
AGXT	ENST00000470255.1	n.643C>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152196 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000392 AC: 60 AN: 152912 Hom.: 0 AF XY: 0.000421 AC XY: 34 AN XY: 80794

Gnomad AFR exome AF: 0.000120

Gnomad AMR exome AF: 0.000163

Gnomad ASJ exome AF: 0.000597

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000442

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000652

Gnomad OTH exome AF: 0.000462

GnomAD4 exome AF: 0.000456 AC: 637 AN: 1397392 Hom.: 0 Cov.: 31 AF XY: 0.000472 AC XY: 325 AN XY: 689124

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.000225

Gnomad4 ASJ exome AF: 0.000359

Gnomad4 EAS exome AF: 0.0000840

Gnomad4 SAS exome AF: 0.000519

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000514

Gnomad4 OTH exome AF: 0.000311

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152314 Hom.: 0 Cov.: 34 AF XY: 0.000497 AC XY: 37 AN XY: 74484

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000618

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000634 Hom.: 0

Bravo AF: 0.000370

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000248 AC: 1

ESP6500EA AF: 0.000514 AC: 4

ExAC AF: 0.000216 AC: 14

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type I Uncertain:4

Uncertain significance, no assertion criteria provided	in vitro	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 27, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 10, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 25, 2017	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 23, 2023

Variant summary: AGXT c.865C>T (p.Arg289Cys) 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 0.00039 in 152912 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in AGXT causing Primary Hyperoxaluria Type 1 (0.00039 vs 0.0024), allowing no conclusion about variant significance. c.865C>T has been reported in the literature in individuals affected with Primary Hyperoxaluria Type 1 (example: Rinalt_1999 and Frishberg_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Primary Hyperoxaluria Type 1. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (example: Pittman_2012). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 07, 2020

This sequence change replaces arginine with cysteine at codon 289 of the AGXT protein (p.Arg289Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs180177290, ExAC 0.1%). This variant has been observed in individual(s) withprimary hyperoxaluria (PMID: 10541294). ClinVar contains an entry for this variant (Variation ID: 204055). Experimental studies have shown that this variant does not substantially affect AGXT protein function (PMID: 22923379). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Benign	-0.064
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.052	T
Polyphen		0.94	P
Vest4		0.72
MVP		0.97
MPC		0.13
ClinPred		0.19	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.36
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs180177290; hg19: chr2-241816972;