rs4426527

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000030.3(AGXT):c.1020A>G(p.Ile340Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,613,084 control chromosomes in the GnomAD database, including 30,860 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I340T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.15 ( 2129 hom., cov: 33)

Exomes 𝑓: 0.19 ( 28731 hom. )

Consequence

AGXT
NM_000030.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:11O:1

Conservation

PhyloP100: 2.93

Publications

65 publications found

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 Gene-Disease associations (from GenCC):

alanine glyoxylate aminotransferase deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
primary hyperoxaluria type 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Myriad Women’s Health, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

AGXT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 130 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: -0.26789 (below the threshold of 3.09). Trascript score misZ: -0.48778 (below the threshold of 3.09). GenCC associations: The gene is linked to alanine glyoxylate aminotransferase deficiency, primary hyperoxaluria type 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022816956).

BP6

Variant 2-240878099-A-G is Benign according to our data. Variant chr2-240878099-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 39486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGXT	NM_000030.3 link	c.1020A>G	p.Ile340Met	missense_variant	Exon 10 of 11	ENST00000307503.4	NP_000021.1	P21549

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4 link	c.1020A>G	p.Ile340Met	missense_variant	Exon 10 of 11	1	NM_000030.3	ENSP00000302620.3		P21549
AGXT	ENST00000470255.1 link	n.798A>G		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.153

AC:

23240

AN:

152056

Hom.:

2127

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0618

Gnomad AMI

AF:

0.248

Gnomad AMR

AF:

0.136

Gnomad ASJ

AF:

0.189

Gnomad EAS

AF:

0.0751

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.242

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.204

Gnomad OTH

AF:

0.167

GnomAD2 exomes

AF:

0.164

AC:

41095

AN:

250624

AF XY:

0.166

show subpopulations

Gnomad AFR exome

AF:

0.0629

Gnomad AMR exome

AF:

0.106

Gnomad ASJ exome

AF:

0.196

Gnomad EAS exome

AF:

0.0857

Gnomad FIN exome

AF:

0.250

Gnomad NFE exome

AF:

0.206

Gnomad OTH exome

AF:

0.180

GnomAD4 exome

AF:

0.193

AC:

281700

AN:

1460910

Hom.:

28731

Cov.:

AF XY:

0.190

AC XY:

138282

AN XY:

726764

show subpopulations

African (AFR)

AF:

0.0617

AC:

2066

AN:

33480

American (AMR)

AF:

0.107

AC:

4806

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.193

AC:

5043

AN:

26128

East Asian (EAS)

AF:

0.0777

AC:

3086

AN:

39700

South Asian (SAS)

AF:

0.106

AC:

9137

AN:

86256

European-Finnish (FIN)

AF:

0.244

AC:

12847

AN:

52604

Middle Eastern (MID)

AF:

0.171

AC:

989

AN:

5768

European-Non Finnish (NFE)

AF:

0.210

AC:

232950

AN:

1111876

Other (OTH)

AF:

0.178

AC:

10776

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

12981

25962

38944

51925

64906

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7960

15920

23880

31840

39800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.153

AC:

23245

AN:

152174

Hom.:

2129

Cov.:

AF XY:

0.152

AC XY:

11317

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.0619

AC:

2571

AN:

41552

American (AMR)

AF:

0.136

AC:

2081

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.189

AC:

657

AN:

3468

East Asian (EAS)

AF:

0.0751

AC:

388

AN:

5168

South Asian (SAS)

AF:

0.105

AC:

504

AN:

4822

European-Finnish (FIN)

AF:

0.242

AC:

2565

AN:

10580

Middle Eastern (MID)

AF:

0.184

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.204

AC:

13851

AN:

67970

Other (OTH)

AF:

0.165

AC:

348

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1005

2010

3016

4021

5026

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

260

520

780

1040

1300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.183

Hom.:

8117

Bravo

AF:

0.143

TwinsUK

AF:

0.214

AC:

793

ALSPAC

AF:

0.204

AC:

786

ESP6500AA

AF:

0.0640

AC:

282

ESP6500EA

AF:

0.208

AC:

1788

ExAC

AF:

0.164

AC:

19922

Asia WGS

AF:

0.0730

AC:

254

AN:

3478

EpiCase

AF:

0.206

EpiControl

AF:

0.202

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary hyperoxaluria, type I

Uncertain:1Benign:6Other:1

Nov 17, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 01, 2004

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Nov 27, 2014

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:in vitro

- -

Oct 30, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 07, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 1703535, 33457257, 24205397, 30341509, 28906061, 15802217) -

not specified

Benign:2

Jun 26, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

0.50

(source)

DANN

Benign

0.091

DEOGEN2

Benign

0.26

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.23

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-2.2

PhyloP100

2.9

PrimateAI

Benign

0.40

PROVEAN

Benign

3.2

REVEL

Benign

0.27

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.054

MPC

0.033

ClinPred

0.0076

GERP RS

2.2

Varity_R

0.32

gMVP

0.76

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over