chr2-240868891-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000030.3(AGXT):c.26C>A(p.Thr9Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00888 in 1,611,766 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T9T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0071 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0091 ( 74 hom. )

Consequence

AGXT
NM_000030.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:10

Conservation

PhyloP100: 0.775

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 was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_000030.3

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 primary hyperoxaluria type 1, alanine glyoxylate aminotransferase deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.007460147).

BP6

Variant 2-240868891-C-A is Benign according to our data. Variant chr2-240868891-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 204016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00709 (1079/152088) while in subpopulation NFE AF = 0.0105 (711/67944). AF 95% confidence interval is 0.00983. There are 6 homozygotes in GnomAd4. There are 504 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGXT	NM_000030.3 link	c.26C>A	p.Thr9Asn	missense_variant	Exon 1 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.26C>A	p.Thr9Asn	missense_variant	Exon 1 of 11	1	NM_000030.3	ENSP00000302620.3		P21549
AGXT	ENST00000472436.1 link	n.46C>A		non_coding_transcript_exon_variant	Exon 1 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.00711

AC:

1080

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00191

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00446

Gnomad ASJ

AF:

0.0176

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00436

Gnomad FIN

AF:

0.0119

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0105

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00919

AC:

2204

AN:

239930

AF XY:

0.00945

show subpopulations

Gnomad AFR exome

AF:

0.00157

Gnomad AMR exome

AF:

0.00639

Gnomad ASJ exome

AF:

0.0130

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0135

Gnomad NFE exome

AF:

0.0120

Gnomad OTH exome

AF:

0.0169

GnomAD4 exome

AF:

0.00906

AC:

13227

AN:

1459678

Hom.:

Cov.:

AF XY:

0.00908

AC XY:

6596

AN XY:

726058

show subpopulations

Gnomad4 AFR exome

AF:

0.00132

AC:

AN:

33434

Gnomad4 AMR exome

AF:

0.00624

AC:

278

AN:

44586

Gnomad4 ASJ exome

AF:

0.0129

AC:

336

AN:

26104

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39638

Gnomad4 SAS exome

AF:

0.00669

AC:

575

AN:

85978

Gnomad4 FIN exome

AF:

0.0133

AC:

695

AN:

52432

Gnomad4 NFE exome

AF:

0.00961

AC:

10685

AN:

1111424

Gnomad4 Remaining exome

AF:

0.00879

AC:

530

AN:

60322

Heterozygous variant carriers

822

1643

2465

3286

4108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

358

716

1074

1432

1790

<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:

0.00709

AC:

1079

AN:

152088

Hom.:

Cov.:

AF XY:

0.00678

AC XY:

504

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00190

AC:

0.00190343

AN:

0.00190343

Gnomad4 AMR

AF:

0.00445

AC:

0.00445084

AN:

0.00445084

Gnomad4 ASJ

AF:

0.0176

AC:

0.0175995

AN:

0.0175995

Gnomad4 EAS

AF:

0.000387

AC:

0.000386847

AN:

0.000386847

Gnomad4 SAS

AF:

0.00436

AC:

0.00436409

AN:

0.00436409

Gnomad4 FIN

AF:

0.0119

AC:

0.0118913

AN:

0.0118913

Gnomad4 NFE

AF:

0.0105

AC:

0.0104645

AN:

0.0104645

Gnomad4 OTH

AF:

0.00426

AC:

0.00426136

AN:

0.00426136

Heterozygous variant carriers

122

183

244

305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00913

Hom.:

Bravo

AF:

0.00649

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00930

AC:

ExAC

AF:

0.00968

AC:

1173

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary hyperoxaluria, type I

Uncertain:1Benign:3

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 27, 2014

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:in vitro

- -

Feb 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AGXT: BP4, BS2 -

Dec 04, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28969594, 27884173, 15849466, 21228398, 20981092, 17495019) -

not specified

Benign:3

Sep 17, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC frequency -

Dec 18, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

4.9

DANN

Benign

0.84

DEOGEN2

Benign

0.18

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0075

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.55

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.0

REVEL

Benign

0.26

Sift

Benign

0.045

Sift4G

Benign

0.18

Polyphen

0.0010

Vest4

0.69

MVP

0.46

MPC

0.036

ClinPred

0.0012

GERP RS

1.4

Varity_R

0.11

gMVP

0.73

Mutation Taster

=89/11

polymorphism

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