rs543486699
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_017570.5(OPLAH):c.2557C>T(p.Arg853Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000236 in 1,612,468 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 0.000013 ( 0 hom., cov: 29)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
OPLAH
NM_017570.5 stop_gained
NM_017570.5 stop_gained
Scores
4
1
1
Clinical Significance
Conservation
PhyloP100: 4.91
Genes affected
OPLAH (HGNC:8149): (5-oxoprolinase, ATP-hydrolysing) The protein encoded by this gene acts as a homodimer, using ATP hydrolysis to catalyze the conversion of 5-oxo-L-proline to L-glutamate. Defects in this gene are a cause of 5-oxoprolinase deficiency (OPLAHD). [provided by RefSeq, Jun 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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 8-144054690-G-A is Pathogenic according to our data. Variant chr8-144054690-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 572337.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OPLAH | NM_017570.5 | c.2557C>T | p.Arg853Ter | stop_gained | 19/27 | ENST00000618853.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OPLAH | ENST00000618853.5 | c.2557C>T | p.Arg853Ter | stop_gained | 19/27 | 1 | NM_017570.5 | P1 | |
OPLAH | ENST00000531027.1 | n.190C>T | non_coding_transcript_exon_variant | 1/2 | 2 | ||||
OPLAH | ENST00000527993.1 | upstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152082Hom.: 0 Cov.: 29
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GnomAD3 exomes AF: 0.00000808 AC: 2AN: 247650Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134898
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GnomAD4 exome AF: 0.0000247 AC: 36AN: 1460268Hom.: 0 Cov.: 33 AF XY: 0.0000220 AC XY: 16AN XY: 726388
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152200Hom.: 0 Cov.: 29 AF XY: 0.0000134 AC XY: 1AN XY: 74404
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
5-Oxoprolinase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 16, 2018 | This sequence change creates a premature translational stop signal (p.Arg853*) in the OPLAH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs543486699, ExAC 0.01%). This variant has not been reported in the literature in individuals with OPLAH-related disease. Loss-of-function variants in OPLAH are known to be pathogenic (PMID: 21651516). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Benign
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
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