rs180177170

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5

The NM_000030.3(AGXT):c.125G>A(p.Gly42Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 1,523,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G42V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000080 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

AGXT
NM_000030.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 1.68

Publications

2 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: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_000030.3

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.832

PP5

Variant 2-240868990-G-A is Pathogenic according to our data. Variant chr2-240868990-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 204074.Status of the report is no_assertion_criteria_provided, 0 stars.

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.125G>A	p.Gly42Glu	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.125G>A	p.Gly42Glu	missense	Exon 1 of 11	ENSP00000302620.3	P21549
AGXT	ENST00000908235.1		c.125G>A	p.Gly42Glu	missense	Exon 1 of 12	ENSP00000578294.1
AGXT	ENST00000908236.1		c.125G>A	p.Gly42Glu	missense	Exon 1 of 12	ENSP00000578295.1

Frequencies

GnomAD3 genomes

AF:

0.00000804

AC:

AN:

124388

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000182

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000808

AC:

AN:

247408

AF XY:

0.0000149

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000643

AC:

AN:

1398688

Hom.:

Cov.:

AF XY:

0.00000576

AC XY:

AN XY:

694984

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31626

American (AMR)

AF:

0.00

AC:

AN:

43040

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24184

East Asian (EAS)

AF:

0.00

AC:

AN:

36824

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83620

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47118

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5474

European-Non Finnish (NFE)

AF:

0.00000748

AC:

AN:

1070120

Other (OTH)

AF:

0.00

AC:

AN:

56682

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000803

AC:

AN:

124486

Hom.:

Cov.:

AF XY:

0.0000164

AC XY:

AN XY:

60900

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

34820

American (AMR)

AF:

0.00

AC:

AN:

12960

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2874

East Asian (EAS)

AF:

0.00

AC:

AN:

4618

South Asian (SAS)

AF:

0.00

AC:

AN:

4188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

222

European-Non Finnish (NFE)

AF:

0.0000182

AC:

AN:

54816

Other (OTH)

AF:

0.00

AC:

AN:

1654

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000664

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary hyperoxaluria, type I (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.12

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.52

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.37

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.83

MetaSVM

Pathogenic

0.83

MutationAssessor

Uncertain

2.8

PhyloP100

1.7

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.63

Sift

Benign

0.13

Sift4G

Benign

0.089

Polyphen

0.57

Vest4

0.38

MVP

0.90

MPC

0.10

ClinPred

0.26

GERP RS

3.5

PromoterAI

0.094

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.32

gMVP

0.92

Mutation Taster

=36/64

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over