chr2-240869202-C-A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000030.3(AGXT):​c.198C>A​(p.Tyr66*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y66Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

AGXT
NM_000030.3 stop_gained

Scores

2
1
4

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: -0.226

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

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 2-240869202-C-A is Pathogenic according to our data. Variant chr2-240869202-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 983726.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
AGXTNM_000030.3 linkc.198C>A p.Tyr66* stop_gained Exon 2 of 11 ENST00000307503.4 NP_000021.1 P21549

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AGXTENST00000307503.4 linkc.198C>A p.Tyr66* stop_gained Exon 2 of 11 1 NM_000030.3 ENSP00000302620.3 P21549

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Primary hyperoxaluria, type I Pathogenic:3
Oct 27, 2023
Clinical Biochemistry Laboratory, Health Services Laboratory
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:curation

ACMG:PVS1 PM2 PP5 -

Dec 28, 2019
Myriad Genetics, Inc.
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 12, 2021
Revvity Omics, Revvity
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
36
DANN
Uncertain
1.0
Eigen
Benign
0.16
Eigen_PC
Benign
-0.11
FATHMM_MKL
Benign
0.49
N
PhyloP100
-0.23
Vest4
0.72
GERP RS
0.29
PromoterAI
-0.026
Neutral
Mutation Taster
=1/199
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.19
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs121908521; hg19: chr2-241808619; API