rs180177155

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The ENST00000307503.4(AGXT):​c.1007T>A​(p.Val336Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,056 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 (★★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

AGXT
ENST00000307503.4 missense

Scores

6
5
8

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 0.0950
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.996
PP5
Variant 2-240878086-T-A is Pathogenic according to our data. Variant chr2-240878086-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 204143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AGXTNM_000030.3 linkuse as main transcriptc.1007T>A p.Val336Asp missense_variant 10/11 ENST00000307503.4 NP_000021.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AGXTENST00000307503.4 linkuse as main transcriptc.1007T>A p.Val336Asp missense_variant 10/111 NM_000030.3 ENSP00000302620 P1
AGXTENST00000470255.1 linkuse as main transcriptn.785T>A non_coding_transcript_exon_variant 2/32

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250634
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135604
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461056
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
726834
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Primary hyperoxaluria, type I Pathogenic:3
Pathogenic, no assertion criteria providedin vitroClinical Biochemistry Laboratory, Health Services LaboratoryNov 27, 2014- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 02, 2024- -
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityDec 08, 2022- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 15, 2023This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 336 of the AGXT protein (p.Val336Asp). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects AGXT function (PMID: 18448374, 22529745). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AGXT protein function. ClinVar contains an entry for this variant (Variation ID: 204143). This missense change has been observed in individuals with primary hyperoxaluria type 1 (PMID: 25629080, 34082749). This variant is present in population databases (rs180177155, gnomAD 0.0009%). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.72
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
CADD
Benign
20
DANN
Benign
0.96
DEOGEN2
Uncertain
0.70
D
Eigen
Benign
-0.21
Eigen_PC
Benign
-0.42
FATHMM_MKL
Benign
0.20
N
LIST_S2
Benign
0.79
T
M_CAP
Pathogenic
0.42
D
MetaRNN
Pathogenic
1.0
D
MetaSVM
Uncertain
0.40
D
MutationAssessor
Uncertain
2.9
M
MutationTaster
Benign
0.0077
A
PrimateAI
Benign
0.46
T
PROVEAN
Uncertain
-3.1
D
REVEL
Pathogenic
0.65
Sift
Uncertain
0.013
D
Sift4G
Benign
0.14
T
Polyphen
0.97
D
Vest4
0.63
MutPred
0.91
Loss of stability (P = 0.2082);
MVP
0.90
MPC
0.20
ClinPred
0.53
D
GERP RS
1.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.68
gMVP
0.95

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs180177155; hg19: chr2-241817503; API