Genetic Variant AGXT:p.Pro11Leu (chr2-240868897-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 5P and 20B. PM1PM5PP2BP4_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 the same amino acid substitution has been previously reported as Likely benign in 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:11O:1

Conservation

PhyloP100: 6.62

Publications

111 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: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

AGXT links:

ENSG00000297735 (HGNC:):

ENSG00000297735 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 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

PM5

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

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=0.0018689036).

BP6

Variant 2-240868897-C-T is Benign according to our data. Variant chr2-240868897-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000030.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGXT	NM_000030.3	MANE Select	c.32C>T	p.Pro11Leu	missense	Exon 1 of 11	NP_000021.1	P21549

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AGXT	ENST00000307503.4	TSL:1 MANE Select	c.32C>T	p.Pro11Leu	missense	Exon 1 of 11	ENSP00000302620.3	P21549
AGXT	ENST00000908235.1		c.32C>T	p.Pro11Leu	missense	Exon 1 of 12	ENSP00000578294.1
AGXT	ENST00000908236.1		c.32C>T	p.Pro11Leu	missense	Exon 1 of 12	ENSP00000578295.1

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

GnomAD2 exomes

AF:

0.147

AC:

36260

AN:

246678

AF XY:

0.149

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 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

African (AFR)

AF:

0.0605

AC:

2024

AN:

33472

American (AMR)

AF:

0.0833

AC:

3721

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.180

AC:

4693

AN:

26130

East Asian (EAS)

AF:

0.000479

AC:

AN:

39692

South Asian (SAS)

AF:

0.0760

AC:

6556

AN:

86216

European-Finnish (FIN)

AF:

0.239

AC:

12531

AN:

52476

Middle Eastern (MID)

AF:

0.164

AC:

945

AN:

5764

European-Non Finnish (NFE)

AF:

0.206

AC:

229214

AN:

1111802

Other (OTH)

AF:

0.168

AC:

10155

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

13826

27652

41479

55305

69131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7756

15512

23268

31024

38780

<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:

0.145

AC:

22086

AN:

152260

Hom.:

2025

Cov.:

AF XY:

0.144

AC XY:

10684

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0604

AC:

2510

AN:

41580

American (AMR)

AF:

0.118

AC:

1801

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.181

AC:

628

AN:

3470

East Asian (EAS)

AF:

0.000967

AC:

AN:

5170

South Asian (SAS)

AF:

0.0742

AC:

358

AN:

4828

European-Finnish (FIN)

AF:

0.237

AC:

2514

AN:

10606

Middle Eastern (MID)

AF:

0.180

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.201

AC:

13650

AN:

67982

Other (OTH)

AF:

0.158

AC:

333

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

995

1990

2986

3981

4976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

244

488

732

976

1220

<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:

0.126

Hom.:

1196

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary hyperoxaluria, type I (6)

not specified (4)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

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

PhyloP100

6.6

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

PromoterAI

0.021

Neutral

(source)

Varity_R

0.70

gMVP

0.89

Mutation Taster

=93/7

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over