chr2-240868897-C-T

Position:

chr2-240868897-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 4P and 20B. PM1PM5BP4_StrongBP6_Very_StrongBA1

The NM_000030.3(AGXT):c.32C>T(p.Pro11Leu) variant causes a missense change. The variant allele was found at a frequency of 0.181 in 1,612,864 control chromosomes in the GnomAD database, including 29,291 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P11H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.15 ( 2025 hom., cov: 33)

Exomes 𝑓: 0.18 ( 27266 hom. )

Consequence

AGXT
NM_000030.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 6.62

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 Benign. Variant got -16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000030.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-240868897-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 204069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018689036).

BP6

Variant 2-240868897-C-T is Benign according to our data. Variant chr2-240868897-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 5641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGXT	NM_000030.3 linkuse as main transcript	c.32C>T	p.Pro11Leu	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.32C>T	p.Pro11Leu	missense_variant	1/11	1	NM_000030.3	P1
AGXT	ENST00000472436.1 linkuse as main transcript	n.52C>T		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes

AF:

0.145

AC:

22081

AN:

152142

Hom.:

2022

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0603

Gnomad AMI

AF:

0.257

Gnomad AMR

AF:

0.118

Gnomad ASJ

AF:

0.181

Gnomad EAS

AF:

0.000965

Gnomad SAS

AF:

0.0733

Gnomad FIN

AF:

0.237

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.201

Gnomad OTH

AF:

0.160

GnomAD3 exomes

AF:

0.147

AC:

36260

AN:

246678

Hom.:

3413

AF XY:

0.149

AC XY:

20008

AN XY:

134068

show subpopulations

Gnomad AFR exome

AF:

0.0604

Gnomad AMR exome

AF:

0.0808

Gnomad ASJ exome

AF:

0.184

Gnomad EAS exome

AF:

0.000327

Gnomad SAS exome

AF:

0.0721

Gnomad FIN exome

AF:

0.245

Gnomad NFE exome

AF:

0.202

Gnomad OTH exome

AF:

0.168

GnomAD4 exome

AF:

0.185

AC:

269858

AN:

1460604

Hom.:

27266

Cov.:

AF XY:

0.182

AC XY:

132039

AN XY:

726568

show subpopulations

Gnomad4 AFR exome

AF:

0.0605

Gnomad4 AMR exome

AF:

0.0833

Gnomad4 ASJ exome

AF:

0.180

Gnomad4 EAS exome

AF:

0.000479

Gnomad4 SAS exome

AF:

0.0760

Gnomad4 FIN exome

AF:

0.239

Gnomad4 NFE exome

AF:

0.206

Gnomad4 OTH exome

AF:

0.168

GnomAD4 genome

AF:

0.145

AC:

22086

AN:

152260

Hom.:

2025

Cov.:

AF XY:

0.144

AC XY:

10684

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0604

Gnomad4 AMR

AF:

0.118

Gnomad4 ASJ

AF:

0.181

Gnomad4 EAS

AF:

0.000967

Gnomad4 SAS

AF:

0.0742

Gnomad4 FIN

AF:

0.237

Gnomad4 NFE

AF:

0.201

Gnomad4 OTH

AF:

0.158

Alfa

AF:

0.140

Hom.:

701

Bravo

AF:

0.134

TwinsUK

AF:

0.214

AC:

792

ALSPAC

AF:

0.200

AC:

769

ESP6500AA

AF:

0.0612

AC:

269

ESP6500EA

AF:

0.203

AC:

1749

ExAC

AF:

0.148

AC:

17959

Asia WGS

AF:

0.0330

AC:

116

AN:

3478

EpiCase

AF:

0.203

EpiControl

AF:

0.199

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary hyperoxaluria, type I

Benign:5Other:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 10, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 29, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Biochemistry Laboratory, Health Services Laboratory	Dec 23, 2023	c.32C>T, although a common polymorphic variant with approximately 64% activity in vitro (PMID:10960483), it can influence the pathogenicity of some AGXT variants, for example see c.836T>C -
Benign, no assertion criteria provided	literature only	OMIM	Jan 25, 2013	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 24, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 24, 2023	Variant summary: AGXT c.32C>T (p.Pro11Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.15 in 246868 control chromosomes, predominantly at a frequency of 0.2 within the Non-Finnish European subpopulation in the gnomAD database, including 2253 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 101 fold of the estimated maximal expected allele frequency for a pathogenic variant in AGXT causing Primary Hyperoxaluria Type 1 phenotype (0.0024), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. However, the variant, c.32C>T, has also been reported in the literature in multiple individuals affected with Primary Hyperoxaluria Type 1, together with two pathogenic variants (VanWoerden_2004, Lorenzo_2006, Kanoun_2013, Ahmed_2022). Clinical and functional data show that this variant leads to a synergistic effect with some common pathogenic variants (e.g. Gly170Arg and p.Ile244Thr), and the presence of this variant in the same chromosome (in cis) is required for their loss of function effect (Lumb_2000, Santana_2003, Monico_2007). Four ClinVar submitters (evaluation after 2014) cite this variant as benign (n=2) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

4.8e-10

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-8.9

REVEL

Uncertain

0.44

Sift

Uncertain

0.015

Sift4G

Uncertain

0.013

Polyphen

1.0

Vest4

0.20

MPC

0.25

ClinPred

0.064

GERP RS

4.4

Varity_R

0.70

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