rs200068769
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000274.4(OAT):c.1192C>T(p.Arg398*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,020 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 Pathogenic (★★).
Frequency
Consequence
NM_000274.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OAT | NM_000274.4 | c.1192C>T | p.Arg398* | stop_gained | Exon 10 of 10 | ENST00000368845.6 | NP_000265.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OAT | ENST00000368845.6 | c.1192C>T | p.Arg398* | stop_gained | Exon 10 of 10 | 1 | NM_000274.4 | ENSP00000357838.5 | ||
OAT | ENST00000539214.5 | c.778C>T | p.Arg260* | stop_gained | Exon 9 of 9 | 1 | ENSP00000439042.1 | |||
OAT | ENST00000471127.1 | n.702C>T | non_coding_transcript_exon_variant | Exon 4 of 4 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152144Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250954Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135800
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461758Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727182
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152262Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74470
ClinVar
Submissions by phenotype
Ornithine aminotransferase deficiency Pathogenic:4
The stop gained variant c.1192C>T (p.Arg398Ter) in OAT gene has been reported in an individual affected with gyrate atrophy of the choroid and the retina (Michaud J et.al.,1995). Experimental studies have shown that this nonsense change leads to a drastic reduction of the OAT enzymatic activity (Doimo M et.al.,2013). This variant has been reported to the ClinVar database as Pathogenic. The p.Arg398Ter variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.000797% is reported in gnomAD. The nucleotide change in OAT is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic -
This sequence change creates a premature translational stop signal (p.Arg398*) in the OAT gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 42 amino acid(s) of the OAT protein. This variant is present in population databases (rs200068769, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with gyrate atrophy of the choroid and the retina (PMID: 7887415). ClinVar contains an entry for this variant (Variation ID: 456519). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects OAT function (PMID: 7887415, 23076989). For these reasons, this variant has been classified as Pathogenic. -
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Hyperornithinemia Pathogenic:1
Variant summary: OAT c.1192C>T (p.Arg398X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. Truncations downstream of this position have been classified as pathogenic in ClinVar and is associated with Gyrate atrophy in HGMD. The variant allele was found at a frequency of 8e-06 in 250954 control chromosomes (gnomAD). c.1192C>T has been reported in the literature in individuals affected with Ornithine Aminotransferase Deficiency (examples: Michaud_1995 and Cleary_2005). These data indicate that the variant is associated with disease. Multiple publications have provided experimental evidence that this variant abolishes the protein function (example: Doimo_2012 and Cleary_2005). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at