chr2-240873044-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The NM_000030.3(AGXT):c.590G>A(p.Arg197Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00453 in 1,613,450 control chromosomes in the GnomAD database, including 207 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. R197W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0041 ( 23 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 184 hom. )

Consequence

AGXT
NM_000030.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.08

Publications

11 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: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 alanine glyoxylate aminotransferase deficiency, primary hyperoxaluria type 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.003585279).

BP6

Variant 2-240873044-G-A is Benign according to our data. Variant chr2-240873044-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0662 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.590G>A	p.Arg197Gln	missense	Exon 5 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.590G>A	p.Arg197Gln	missense	Exon 5 of 11	ENSP00000302620.3	P21549
AGXT	ENST00000908235.1		c.590G>A	p.Arg197Gln	missense	Exon 5 of 12	ENSP00000578294.1
AGXT	ENST00000908236.1		c.590G>A	p.Arg197Gln	missense	Exon 5 of 12	ENSP00000578295.1

Frequencies

GnomAD3 genomes

AF:

0.00411

AC:

626

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0723

Gnomad SAS

AF:

0.0294

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.00573

GnomAD2 exomes

AF:

0.0112

AC:

2796

AN:

249144

AF XY:

0.0119

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00521

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.0866

Gnomad FIN exome

AF:

0.000373

Gnomad NFE exome

AF:

0.000913

Gnomad OTH exome

AF:

0.00474

GnomAD4 exome

AF:

0.00457

AC:

6681

AN:

1461188

Hom.:

184

Cov.:

AF XY:

0.00528

AC XY:

3839

AN XY:

726962

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33474

American (AMR)

AF:

0.00483

AC:

216

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26122

East Asian (EAS)

AF:

0.0767

AC:

3041

AN:

39672

South Asian (SAS)

AF:

0.0279

AC:

2401

AN:

86172

European-Finnish (FIN)

AF:

0.000678

AC:

AN:

53100

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000585

AC:

650

AN:

1111804

Other (OTH)

AF:

0.00528

AC:

319

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.412

Heterozygous variant carriers

323

646

968

1291

1614

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

294

392

490

<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:

0.00410

AC:

624

AN:

152262

Hom.:

Cov.:

AF XY:

0.00496

AC XY:

369

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41544

American (AMR)

AF:

0.00189

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0723

AC:

373

AN:

5160

South Asian (SAS)

AF:

0.0292

AC:

141

AN:

4822

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000618

AC:

AN:

68012

Other (OTH)

AF:

0.00567

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

125

156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.00317

Hom.:

Bravo

AF:

0.00416

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.0114

AC:

1382

Asia WGS

AF:

0.0370

AC:

129

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000830

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 (4)

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.23

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.23

MetaRNN

Benign

0.0036

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.1

PhyloP100

1.1

PrimateAI

Benign

0.31

PROVEAN

Benign

1.4

REVEL

Uncertain

0.36

Sift

Benign

0.98

Sift4G

Benign

0.81

Polyphen

0.0

Vest4

0.076

MPC

0.035

ClinPred

0.019

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.44

Mutation Taster

=89/11

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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