chr2-240868971-C-T

Position:

chr2-240868971-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000030.3(AGXT):c.106C>T(p.Arg36Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000497 in 1,609,116 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R36H) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

AGXT
NM_000030.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 3.92

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 18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 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 chr2-240868972-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 204072.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 2-240868971-C-T is Pathogenic according to our data. Variant chr2-240868971-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188957.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 linkuse as main transcript	c.106C>T	p.Arg36Cys	missense_variant	1/11	ENST00000307503.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGXT	ENST00000307503.4 linkuse as main transcript	c.106C>T	p.Arg36Cys	missense_variant	1/11	1	NM_000030.3	P1
AGXT	ENST00000472436.1 linkuse as main transcript	n.126C>T		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes

AF:

0.0000200

AC:

AN:

149816

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000506

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247828

Hom.:

AF XY:

0.00000743

AC XY:

AN XY:

134652

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1459300

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725874

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000513

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000200

AC:

AN:

149816

Hom.:

Cov.:

AF XY:

0.0000273

AC XY:

AN XY:

73212

show subpopulations

Gnomad4 AFR

AF:

0.0000506

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary hyperoxaluria, type I

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 23, 2024	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Sep 05, 2014	- -
Pathogenic, no assertion criteria provided	in vitro	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 27, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 15, 2022	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 36 of the AGXT protein (p.Arg36Cys). This variant is present in population databases (rs180177157, gnomAD 0.006%). This missense change has been observed in individuals with primary hyperoxaluria (PMID: 15356974, 24988064). ClinVar contains an entry for this variant (Variation ID: 188957). 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: 17495019, 22923379, 24718375). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Uncertain

0.36

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-6.8

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.91

MutPred

0.92

Gain of catalytic residue at P35 (P = 0.0286);

MVP

0.97

MPC

0.28

ClinPred

0.98

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.89

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