rs180177227

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000030.3(AGXT):c.481G>A(p.Gly161Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,600,490 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 (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

AGXT
NM_000030.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 8.52

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 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.996

PP5

Variant 2-240871406-G-A is Pathogenic according to our data. Variant chr2-240871406-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 204105.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.481G>A	p.Gly161Ser	missense_variant	4/11	ENST00000307503.4	NP_000021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
AGXT	ENST00000307503.4 linkuse as main transcript	c.481G>A	p.Gly161Ser	missense_variant	4/11	1	NM_000030.3	ENSP00000302620	P1
AGXT	ENST00000472436.1 linkuse as main transcript	n.501G>A		non_coding_transcript_exon_variant	4/5	2
AGXT	ENST00000476698.1 linkuse as main transcript	n.218G>A		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152184

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000177

AC:

AN:

226372

Hom.:

AF XY:

0.0000245

AC XY:

AN XY:

122422

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:

0.0000395

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1448306

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

719106

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000387

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000194

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary hyperoxaluria, type I

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 12, 2020	- -
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	Mar 22, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Chinese Inherited Urolithiasis Consortium, The Affiliated Yantai Yuhuangding Hospital of Qingdao University	Aug 26, 2024	Variant_type:missense/MutationTaster:Disease_causing/CADD:Damaging/phyloP:Conserved/phastCons:Conserved/gnomAD_exome_EastAsian:0/ExAC_EastAsian:0/dbSNP:rs180177227 -

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

Mar 14, 2023

Variant summary: AGXT c.481G>A (p.Gly161Ser) results in a non-conservative amino acid change located in the Aminotransferase class V domain (IPR000192) of the encoded protein sequence. Three variants, namely p.Gly161Arg/Ser/Cys affecting this residue have been reported among PH1 patients: p.G161R on the major allele and p.G161S and p.G161C on the minor allele. These mutations are predicted to interfere with AGT folding promoting protein aggregation (reviewed in Mandrile_2023). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 226372 control chromosomes. c.481G>A has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in individuals affected with Primary Hyperoxaluria Type 1 (example, Daga_2018, Williams_2015). These data indicate that the variant is likely to be associated with disease. Three 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. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 12, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 161 of the AGXT protein (p.Gly161Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with primary hyperoxaluria type 1 (PMID: 17460142, 25629080, 28893421). ClinVar contains an entry for this variant (Variation ID: 204105). 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 not expected to disrupt AGXT protein function. Experimental studies have shown that this missense change affects AGXT function (PMID: 24055001). This variant disrupts the p.Gly161 amino acid residue in AGXT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25629080; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

1.0

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-5.1

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.99

MutPred

0.99

Gain of disorder (P = 0.0919);

MVP

0.95

MPC

0.24

ClinPred

0.98

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.94

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