dbSNP rs121908529: AGXT:p.Gly170Arg (chr2-240871433-G-A) – ACMG Classification: Pathogenic (26 pts)

Variant summary

Our verdict is Pathogenic. The variant received 26 ACMG points: 27P and 1B. PS1_Very_StrongPS3PM1PP2PP3_StrongPP5_Very_StrongBS2_Supporting

The NM_000030.3(AGXT):c.508G>A(p.Gly170Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000951 in 1,592,184 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000803508: Well-established functional studies show a deleterious effect on the activity of the minor allele (AGT-Mi). (PMID:19479957) (PMID:17495019) (PMID:10960483)." and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G170G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00098 ( 3 hom. )

Consequence

AGXT
NM_000030.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:25O:1

Conservation

PhyloP100: 8.49

Publications

172 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 26 ACMG points.

PS1

Transcript NM_000030.3 (AGXT) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000803508: Well-established functional studies show a deleterious effect on the activity of the minor allele (AGT-Mi). (PMID:19479957) (PMID:17495019) (PMID:10960483).; SCV000914911: Liver biopsies from affected probands found that homozygotes for the p.Gly170Arg had a median AGT activity at 41% of normal, consistent with a less severe phenotype (Harambat et al. 2010).; SCV000966875: "In vitro functional studies provide some evidence that the p.Gly170Arg variant may impact protein function by mislocalization and decreased catalytic activity (Fargue 2013)."; SCV005879872: Functional analyses demonstrate when found in cis with benign polymorphism, p.Pro11Leu, results in mistargeting of the AGT enzyme to the mitochondria rather than the peroxisomes (Coulter-Mackie 2005, Lumb 1999, Lumb 2000). PMID: 15802217. PMID: 10960689. PMID: 10960483.; SCV000617630: Functional studies demonstrate that G170R, when present in cis with the P11L AGXT variant, unmasks the cryptic mitochondrial targeting sequence encoded by P11L and results in the mistargeting of the AGT enzyme to the mitochondria instead of to the peroxisomes (Lumb et al., 2000; Montioli et al., 2014); SCV000944322: Experimental studies have shown that this missense change affects AGXT function (PMID: 10960483, 17110443, 23229545).; SCV000693979: Functional studies showed that G170R causes a folding defect leading to an erroneous targeting to mitochondria, where the enzyme cannot perform glyoxylate detoxification.; SCV004115838: Functional studies indicate this variant results in impaired enzymatic activity and mislocalization of the AGT protein (Purdue et al. 1990. PubMed ID: 1703535; Lumb et al. 2000. PubMed ID: 10960483; Coulter-Mackie et al. 2005. PubMed ID: 15802217).

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

PP5

Variant 2-240871433-G-A is Pathogenic according to our data. Variant chr2-240871433-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 40166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.508G>A	p.Gly170Arg	missense	Exon 4 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.508G>A	p.Gly170Arg	missense	Exon 4 of 11	ENSP00000302620.3	P21549
AGXT	ENST00000908235.1		c.508G>A	p.Gly170Arg	missense	Exon 4 of 12	ENSP00000578294.1
AGXT	ENST00000908236.1		c.508G>A	p.Gly170Arg	missense	Exon 4 of 12	ENSP00000578295.1

Frequencies

GnomAD3 genomes

AF:

0.000631

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000560

AC:

118

AN:

210718

AF XY:

0.000643

show subpopulations

Gnomad AFR exome

AF:

0.0000779

Gnomad AMR exome

AF:

0.000131

Gnomad ASJ exome

AF:

0.000216

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000166

Gnomad NFE exome

AF:

0.00110

Gnomad OTH exome

AF:

0.000564

GnomAD4 exome

AF:

0.000985

AC:

1418

AN:

1440004

Hom.:

Cov.:

AF XY:

0.000972

AC XY:

694

AN XY:

714152

show subpopulations

African (AFR)

AF:

0.000242

AC:

AN:

33110

American (AMR)

AF:

0.000119

AC:

AN:

41854

Ashkenazi Jewish (ASJ)

AF:

0.000234

AC:

AN:

25684

East Asian (EAS)

AF:

0.00

AC:

AN:

38646

South Asian (SAS)

AF:

0.0000727

AC:

AN:

82514

European-Finnish (FIN)

AF:

0.000294

AC:

AN:

50940

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00122

AC:

1344

AN:

1101978

Other (OTH)

AF:

0.000554

AC:

AN:

59576

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

143

214

286

357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.000631

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000498

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41448

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000376

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00116

AC:

AN:

68020

Other (OTH)

AF:

0.000957

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000958

Hom.:

Bravo

AF:

0.000525

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000440

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary hyperoxaluria, type I (17)

not provided (7)

AGXT-related disorder (1)

Primary hyperoxaluria (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

3.8

PhyloP100

8.5

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-7.6

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.018

Polyphen

1.0

Vest4

0.95

MutPred

0.90

Loss of catalytic residue at G170 (P = 0.1531)

MVP

0.95

MPC

0.26

ClinPred

0.87

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.98

Mutation Taster

=4/96

disease causing (ClinVar)

(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