NM_000030.3:c.865C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PP2PP3

The NM_000030.3(AGXT):c.865C>T(p.Arg289Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000452 in 1,549,706 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R289H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00046 ( 0 hom. )

Consequence

AGXT
NM_000030.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: -0.0110

Publications

5 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: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 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, 0.77

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.865C>T	p.Arg289Cys	missense	Exon 9 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.865C>T	p.Arg289Cys	missense	Exon 9 of 11	ENSP00000302620.3	P21549
AGXT	ENST00000908235.1		c.1138C>T	p.Arg380Cys	missense	Exon 10 of 12	ENSP00000578294.1
AGXT	ENST00000908236.1		c.1054C>T	p.Arg352Cys	missense	Exon 10 of 12	ENSP00000578295.1

Frequencies

GnomAD3 genomes

AF:

0.000421

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000392

AC:

AN:

152912

AF XY:

0.000421

show subpopulations

Gnomad AFR exome

AF:

0.000120

Gnomad AMR exome

AF:

0.000163

Gnomad ASJ exome

AF:

0.000597

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000652

Gnomad OTH exome

AF:

0.000462

GnomAD4 exome

AF:

0.000456

AC:

637

AN:

1397392

Hom.:

Cov.:

AF XY:

0.000472

AC XY:

325

AN XY:

689124

show subpopulations

African (AFR)

AF:

0.0000633

AC:

AN:

31576

American (AMR)

AF:

0.000225

AC:

AN:

35586

Ashkenazi Jewish (ASJ)

AF:

0.000359

AC:

AN:

25082

East Asian (EAS)

AF:

0.0000840

AC:

AN:

35720

South Asian (SAS)

AF:

0.000519

AC:

AN:

79074

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48514

Middle Eastern (MID)

AF:

0.000351

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.000514

AC:

554

AN:

1078214

Other (OTH)

AF:

0.000311

AC:

AN:

57936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

101

134

168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000420

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41578

American (AMR)

AF:

0.000653

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000618

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2112

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:

0.000617

Hom.:

Bravo

AF:

0.000370

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000248

AC:

ESP6500EA

AF:

0.000514

AC:

ExAC

AF:

0.000216

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary hyperoxaluria, type I (6)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

Eigen

Benign

-0.064

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.77

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.8

PhyloP100

-0.011

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-4.3

REVEL

Pathogenic

0.70

Sift

Uncertain

0.013

Sift4G

Uncertain

0.052

Polyphen

0.94

Vest4

0.72

MVP

0.97

MPC

0.13

ClinPred

0.19

GERP RS

1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.36

gMVP

0.84

Mutation Taster

=19/81

disease causing

(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