2-240869350-G-A

Position:

chr2-240869350-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000030.3(AGXT):c.346G>A(p.Gly116Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000939 in 1,597,378 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

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

AGXT
NM_000030.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 8.86

Variant links:

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]

AGXT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.937

PP5

Variant 2-240869350-G-A is Pathogenic according to our data. Variant chr2-240869350-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240869350-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGXT	NM_000030.3 linkuse as main transcript	c.346G>A	p.Gly116Arg	missense_variant	2/11	ENST00000307503.4	NP_000021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4 linkuse as main transcript	c.346G>A	p.Gly116Arg	missense_variant	2/11	1	NM_000030.3	ENSP00000302620	P1
AGXT	ENST00000472436.1 linkuse as main transcript	n.366G>A		non_coding_transcript_exon_variant	2/5	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000426

AC:

AN:

234802

Hom.:

AF XY:

0.00000793

AC XY:

AN XY:

126096

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000949

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000830

AC:

AN:

1445164

Hom.:

Cov.:

AF XY:

0.0000112

AC XY:

AN XY:

716822

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000120

Gnomad4 FIN exome

AF:

0.0000386

Gnomad4 NFE exome

AF:

0.00000816

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000143

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary hyperoxaluria, type I

Pathogenic:5

Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 03, 2020	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Oct 16, 2014	- -
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 24, 2024	- -
Likely pathogenic, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 14, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 116 of the AGXT protein (p.Gly116Arg). This variant is present in population databases (rs180177207, gnomAD 0.003%). This missense change has been observed in individual(s) with primary hyperoxaluria (PMID: 10453743, 17460142, 25629080, 26252291, 33691640). 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: 189021). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AGXT protein function. For these reasons, this variant has been classified as Pathogenic. -

Abnormality of metabolism/homeostasis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

0.93

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

0.99

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.0

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.86

MutPred

0.95

Gain of methylation at G116 (P = 0.0405);

MVP

0.95

MPC

0.24

ClinPred

0.93

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.99

gMVP

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over