Genetic Variant AGXT:p.Leu43AlafsTer125 (chr2-240868985-C-CG) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000030.3(AGXT):c.126dupG(p.Leu43AlafsTer125) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000013 in 1,534,288 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000079 ( 0 hom., cov: 34)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

AGXT
NM_000030.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 3.81

Publications

3 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: G2P, Myriad Women’s Health, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

AGXT links:

ENSG00000297735 (HGNC:):

ENSG00000297735 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-240868985-C-CG is Pathogenic according to our data. Variant chr2-240868985-C-CG is described in ClinVar as Pathogenic. ClinVar VariationId is 554314.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGXT	NM_000030.3 link	c.126dupG	p.Leu43AlafsTer125	frameshift_variant	Exon 1 of 11	ENST00000307503.4	NP_000021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4 link	c.126dupG	p.Leu43AlafsTer125	frameshift_variant	Exon 1 of 11	1	NM_000030.3	ENSP00000302620.3

Frequencies

GnomAD3 genomes

AF:

0.00000794

AC:

AN:

125882

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000765

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.10e-7

AC:

AN:

1408406

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

700096

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31940

American (AMR)

AF:

0.00

AC:

AN:

43304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24476

East Asian (EAS)

AF:

0.00

AC:

AN:

37352

South Asian (SAS)

AF:

0.0000119

AC:

AN:

84044

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48008

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5536

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1076468

Other (OTH)

AF:

0.00

AC:

AN:

57278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000794

AC:

AN:

125882

Hom.:

Cov.:

AF XY:

0.0000163

AC XY:

AN XY:

61446

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

35068

American (AMR)

AF:

0.0000765

AC:

AN:

13064

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2928

East Asian (EAS)

AF:

0.00

AC:

AN:

4644

South Asian (SAS)

AF:

0.00

AC:

AN:

4238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7654

Middle Eastern (MID)

AF:

0.00

AC:

AN:

242

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

55666

Other (OTH)

AF:

0.00

AC:

AN:

1660

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary hyperoxaluria, type I

Pathogenic:2

Oct 16, 2017

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Oct 27, 2023

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

ACMG:PVS1 PM2 PM3 PP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.8

Mutation Taster

=7/193

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over