dbSNP rs34116584: AGXT:p.Pro11His (chr2-240868897-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PM1PM5PP2BP4_ModerateBP6BS2_Supporting

The NM_000030.3(AGXT):c.32C>A(p.Pro11His) variant causes a missense change. The variant allele was found at a frequency of 0.000582 in 1,612,894 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P11S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00059 ( 3 hom. )

Consequence

AGXT
NM_000030.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

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: Uncertain_significance. The variant received 1 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=0.2520356).

BP6

Variant 2-240868897-C-A is Benign according to our data. Variant chr2-240868897-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 204018.

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.32C>A	p.Pro11His	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>A	p.Pro11His	missense	Exon 1 of 11	ENSP00000302620.3	P21549
AGXT	ENST00000908235.1		c.32C>A	p.Pro11His	missense	Exon 1 of 12	ENSP00000578294.1
AGXT	ENST00000908236.1		c.32C>A	p.Pro11His	missense	Exon 1 of 12	ENSP00000578295.1

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000381

AC:

AN:

246678

AF XY:

0.000388

show subpopulations

Gnomad AFR exome

AF:

0.0000626

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00142

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000473

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000592

AC:

865

AN:

1460620

Hom.:

Cov.:

AF XY:

0.000607

AC XY:

441

AN XY:

726580

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33472

American (AMR)

AF:

0.000246

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.000756

AC:

AN:

39692

South Asian (SAS)

AF:

0.000232

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52484

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000687

AC:

764

AN:

1111810

Other (OTH)

AF:

0.000530

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

105

157

210

262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.000479

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.000240

AC:

AN:

41580

American (AMR)

AF:

0.000523

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000580

AC:

AN:

5170

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000691

AC:

AN:

67990

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.00916

Hom.:

1196

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.000420

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000417

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary hyperoxaluria, type I (2)

AGXT-related disorder (1)

Alanine glyoxylate aminotransferase deficiency (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.78

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.71

M_CAP

Pathogenic

0.60

MetaRNN

Benign

0.25

MetaSVM

Pathogenic

0.81

MutationAssessor

Pathogenic

3.2

PhyloP100

6.6

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-8.1

REVEL

Uncertain

0.56

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.48

MutPred

0.43

Loss of glycosylation at P11 (P = 0.0183)

MVP

0.99

MPC

0.26

ClinPred

0.27

GERP RS

4.4

PromoterAI

0.027

Neutral

(source)

Varity_R

0.78

gMVP

0.86

Mutation Taster

=88/12

polymorphism

(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