rs386833600
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000274.4(OAT):c.192_193delAG(p.Gly65fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,614 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000028 ( 0 hom. )
Consequence
OAT
NM_000274.4 frameshift
NM_000274.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.55
Genes affected
OAT (HGNC:8091): (ornithine aminotransferase) This gene encodes the mitochondrial enzyme ornithine aminotransferase, which is a key enzyme in the pathway that converts arginine and ornithine into the major excitatory and inhibitory neurotransmitters glutamate and GABA. Mutations that result in a deficiency of this enzyme cause the autosomal recessive eye disease Gyrate Atrophy. Alternatively spliced transcript variants encoding different isoforms have been described. Related pseudogenes have been defined on the X chromosome. [provided by RefSeq, Jan 2010]
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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 10-124411978-CCT-C is Pathogenic according to our data. Variant chr10-124411978-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124411978-CCT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OAT | NM_000274.4 | c.192_193delAG | p.Gly65fs | frameshift_variant | 2/10 | ENST00000368845.6 | NP_000265.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OAT | ENST00000368845.6 | c.192_193delAG | p.Gly65fs | frameshift_variant | 2/10 | 1 | NM_000274.4 | ENSP00000357838.5 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251476Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135910
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GnomAD4 exome AF: 0.0000281 AC: 41AN: 1461434Hom.: 0 AF XY: 0.0000234 AC XY: 17AN XY: 727066
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74322
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ornithine aminotransferase deficiency Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 27, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 01, 2021 | - - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 1992 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 02, 2024 | This sequence change creates a premature translational stop signal (p.Gly65Lysfs*15) in the OAT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OAT are known to be pathogenic (PMID: 1737786, 23076989). This variant is present in population databases (rs386833600, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with clinical features of gyrate atrophy (PMID: 1609808). This variant is also known as 2-bp deletion (AG). ClinVar contains an entry for this variant (Variation ID: 178). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 22, 2024 | The OAT c.192_193delAG (p.Gly65LysfsTer15) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant is not observed at a significant frequency in version 4.1.0 of the Genome Aggregation Database. The p.Gly65LysfsTer15 variant was identified in trans with a pathogenic variant in at least one individual with a phenotype consistent with ornithine aminotransferase deficiency (PMID:1609808). Functional studies conducted in patient fibroblasts demonstrated that this variant impacts protein function (PMID:1609808). Based on the available evidence, the c.192_193delAG (p.Gly65LysfsTer15) variant is classified as pathogenic for ornithine aminotransferase deficiency. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at