2-240878076-A-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000030.3(AGXT):c.997A>T(p.Arg333Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R333R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
AGXT
NM_000030.3 stop_gained
NM_000030.3 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 3.63
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 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 2-240878076-A-T is Pathogenic according to our data. Variant chr2-240878076-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 204142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AGXT | NM_000030.3 | c.997A>T | p.Arg333Ter | stop_gained | 10/11 | ENST00000307503.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGXT | ENST00000307503.4 | c.997A>T | p.Arg333Ter | stop_gained | 10/11 | 1 | NM_000030.3 | P1 | |
AGXT | ENST00000470255.1 | n.775A>T | non_coding_transcript_exon_variant | 2/3 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: 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 provided | clinical testing | Natera, Inc. | Mar 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 28, 2022 | - - |
Pathogenic, no assertion criteria provided | research | Clinical Biochemistry Laboratory, Health Services Laboratory | Nov 27, 2014 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 05, 2019 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in AGXT are known to be pathogenic (PMID: 19479957). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in multiple individuals affected with primary hyperoxaluria, type 1 (PMID: 10541294, 27644547, Invitae). ClinVar contains an entry for this variant (Variation ID: 204142). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg333*) in the AGXT gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at