2-240871398-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000030.3(AGXT):c.473C>T(p.Ser158Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000829 in 1,448,276 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S158S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

AGXT
NM_000030.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 6.72

Publications

10 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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, 0.996

PP5

Variant 2-240871398-C-T is Pathogenic according to our data. Variant chr2-240871398-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 204103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGXT	NM_000030.3 link	c.473C>T	p.Ser158Leu	missense_variant	Exon 4 of 11	ENST00000307503.4	NP_000021.1	P21549

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AGXT	ENST00000307503.4 link	c.473C>T	p.Ser158Leu	missense_variant	Exon 4 of 11	1	NM_000030.3	ENSP00000302620.3	P21549
AGXT	ENST00000472436.1 link	n.493C>T		non_coding_transcript_exon_variant	Exon 4 of 5	2
AGXT	ENST00000476698.1 link	n.210C>T		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000441

AC:

AN:

226530

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000308

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000829

AC:

AN:

1448276

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

719190

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33274

American (AMR)

AF:

0.0000232

AC:

AN:

43122

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25836

East Asian (EAS)

AF:

0.00

AC:

AN:

39052

South Asian (SAS)

AF:

0.00

AC:

AN:

83508

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00000994

AC:

AN:

1106314

Other (OTH)

AF:

0.00

AC:

AN:

59894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary hyperoxaluria, type I

Pathogenic:6

Jan 17, 2019

Yale Center for Mendelian Genomics, Yale University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Nov 27, 2014

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:in vitro

- -

Jul 07, 2017

GenePathDx, GenePath diagnostics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 17, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 20, 2016

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. -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Feb 09, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30655312, 22923379, 15849466, 18782763, 22018727, 30541997) -

Dec 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 158 of the AGXT protein (p.Ser158Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with primary hyperoxaluria type 1 (PMID: 15849466, 17460142, 17495019, 23430879, 25629080, 30541997). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 204103). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AGXT protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects AGXT function (PMID: 18782763, 22018727, 22923379). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

1.0

MetaSVM

Uncertain

0.67

MutationAssessor

Pathogenic

3.4

PhyloP100

6.7

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.98

MutPred

0.94

Loss of disorder (P = 0.0172);

MVP

0.96

MPC

0.24

ClinPred

0.99

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.98

gMVP

0.96

Mutation Taster

=12/88

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over