2-240869004-G-A

Position:

chr2-240869004-G-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000307503.4(AGXT):c.139G>A(p.Gly47Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000122 in 1,475,840 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. G47E) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

AGXT
ENST00000307503.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.63

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 20 ACMG points.

PS1

Transcript ENST00000307503.4 (AGXT) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 2681194

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-240869005-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2681153.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant 2-240869004-G-A is Pathogenic according to our data. Variant chr2-240869004-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 204076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGXT	NM_000030.3 linkuse as main transcript	c.139G>A	p.Gly47Arg	missense_variant	1/11	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.139G>A	p.Gly47Arg	missense_variant	1/11	1	NM_000030.3	ENSP00000302620	P1
AGXT	ENST00000472436.1 linkuse as main transcript	n.159G>A		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes

AF:

0.0000256

AC:

AN:

117034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000803

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:

0.0000394

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000247

AC:

AN:

243256

Hom.:

AF XY:

0.0000227

AC XY:

AN XY:

132418

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000147

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:

0.00000919

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1358806

Hom.:

Cov.:

AF XY:

0.0000133

AC XY:

AN XY:

674372

show subpopulations

Gnomad4 AFR exome

AF:

0.0000325

Gnomad4 AMR exome

AF:

0.000120

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000766

Gnomad4 OTH exome

AF:

0.0000184

GnomAD4 genome

AF:

0.0000256

AC:

AN:

117034

Hom.:

Cov.:

AF XY:

0.0000349

AC XY:

AN XY:

57356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000803

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000394

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary hyperoxaluria, type I

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 10, 2023	- -
Pathogenic, no assertion criteria provided	in vitro	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 27, 2014	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 47 of the AGXT protein (p.Gly47Arg). This variant is present in population databases (rs180177173, gnomAD 0.02%). This missense change has been observed in individual(s) with type 1 primary hyperoxaluria (PMID: 17460142, 20564000). ClinVar contains an entry for this variant (Variation ID: 204076). 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: 24718375, 26149463). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Uncertain

0.34

Eigen_PC

Benign

0.083

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.71

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

4.2

MutationTaster

Benign

1.0

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-7.1

REVEL

Uncertain

0.64

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.77

MutPred

0.92

Gain of MoRF binding (P = 0.007);

MVP

0.95

MPC

0.27

ClinPred

0.99

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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