rs386833623
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000274.4(OAT):c.991C>T(p.Arg331Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,612,406 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )
Consequence
OAT
NM_000274.4 stop_gained
NM_000274.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.62
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 10-124401749-G-A is Pathogenic according to our data. Variant chr10-124401749-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 56141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124401749-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OAT | NM_000274.4 | c.991C>T | p.Arg331Ter | stop_gained | 8/10 | ENST00000368845.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OAT | ENST00000368845.6 | c.991C>T | p.Arg331Ter | stop_gained | 8/10 | 1 | NM_000274.4 | P1 | |
OAT | ENST00000539214.5 | c.577C>T | p.Arg193Ter | stop_gained | 7/9 | 1 | |||
OAT | ENST00000467675.5 | n.792C>T | non_coding_transcript_exon_variant | 7/7 | 5 | ||||
OAT | ENST00000471127.1 | n.501C>T | non_coding_transcript_exon_variant | 2/4 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152060Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000240 AC: 6AN: 250384Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135366
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GnomAD4 exome AF: 0.0000151 AC: 22AN: 1460346Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 726546
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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:5
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 31, 2022 | - - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | This sequence change creates a premature translational stop signal (p.Arg331*) 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 (rs386833623, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with gyrate atrophy (PMID: 23076989). ClinVar contains an entry for this variant (Variation ID: 56141). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 09, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 29, 2020 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 02, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23076989, 34426522) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at