rs180177221
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000030.3(AGXT):c.447_454delGCTGCTGT(p.Leu151fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
AGXT
NM_000030.3 frameshift
NM_000030.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.82
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 2-240871369-AGTGCTGCT-A is Pathogenic according to our data. Variant chr2-240871369-AGTGCTGCT-A is described in ClinVar as [Pathogenic]. Clinvar id is 204185.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 |
---|---|---|---|---|---|---|---|---|
AGXT | NM_000030.3 | c.447_454delGCTGCTGT | p.Leu151fs | frameshift_variant | 4/11 | ENST00000307503.4 | NP_000021.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AGXT | ENST00000307503.4 | c.447_454delGCTGCTGT | p.Leu151fs | frameshift_variant | 4/11 | 1 | NM_000030.3 | ENSP00000302620.3 | ||
AGXT | ENST00000472436.1 | n.467_474delGCTGCTGT | non_coding_transcript_exon_variant | 4/5 | 2 | |||||
AGXT | ENST00000476698.1 | n.184_191delGCTGCTGT | non_coding_transcript_exon_variant | 1/4 | 5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary hyperoxaluria, type I Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 11, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Jul 22, 2023 | The observed frameshift c.447_454delp.Leu151AsnfsTer14 variant in AGXT gene has been reported previously in individuals affected with Primary Hyperoxaluria Type 1 Dutta AK, et al., 2016; Williams E, Rumsby G., 2007. The p.Leu151AsnfsTer14 variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. This variant causes a frameshift starting with codon Leucine 151, changes this amino acid to Asparagine residue, and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Leu151AsnfsTer14. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 18, 2016 | - - |
Pathogenic, no assertion criteria provided | research | Clinical Biochemistry Laboratory, Health Services Laboratory | Nov 27, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 27, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 24, 2023 | - - |
Primary hyperoxaluria Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 30, 2019 | Variant summary: AGXT c.447_454delGCTGCTGT (p.Leu151AsnfsX14) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 213810 control chromosomes (gnomAD) but has been reported in the literature in multiple individuals (primarily of Asian origin) affected with Primary Hyperoxaluria Type 1 (Williams_2007, Dutta_2016). These data indicate that the variant is very likely to be associated with disease. Enzymatic activity measured from a homozygous individual harboring this variant show 6% of mean control activity (Williams_2007). A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 05, 2023 | This sequence change creates a premature translational stop signal (p.Leu151Asnfs*14) in the AGXT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AGXT are known to be pathogenic (PMID: 19479957). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with primary hyperoxaluria (PMID: 17495019, 27512303). This variant is also known as c.445_452delGTGCTGCT. ClinVar contains an entry for this variant (Variation ID: 204185). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at