rs72557929
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_001395413.1(POR):c.1208G>A(p.Arg403His) variant causes a missense change. The variant allele was found at a frequency of 0.000186 in 1,602,474 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001395413.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POR | NM_001395413.1 | c.1208G>A | p.Arg403His | missense_variant | Exon 11 of 16 | ENST00000461988.6 | NP_001382342.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152140Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000103 AC: 25AN: 243688Hom.: 0 AF XY: 0.000105 AC XY: 14AN XY: 132820
GnomAD4 exome AF: 0.000190 AC: 275AN: 1450334Hom.: 1 Cov.: 43 AF XY: 0.000185 AC XY: 133AN XY: 719510
GnomAD4 genome AF: 0.000151 AC: 23AN: 152140Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74320
ClinVar
Submissions by phenotype
Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency Uncertain:2
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 406 of the POR protein (p.Arg406His). This variant is present in population databases (rs72557929, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with POR-related conditions. ClinVar contains an entry for this variant (Variation ID: 911635). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POR protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on POR function (PMID: 18230729, 18551037). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided Uncertain:2
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not reported as pathogenic or benign in association with a disease to our our knowledge. However, identified in a healthy population and functional studies demonstrate a moderate reduction in protein activities in multiple enzymatic assays (Huang et al., 2008; Agrawal et al., 2008); This variant is associated with the following publications: (PMID: 27068427, 25133307, 18433346, 24847272, 23353702, 18930113, 18551037, 18230729) -
The POR c.1217G>A; p.Arg406His variant (rs72557929) is reported in the literature in a cohort of healthy individuals (Huang 2008). This variant is found in the general population with an overall allele frequency of 0.012% (32/275012 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.184). Functional analyses suggest the p.Arg406His variant protein supports normal activity of partner proteins but exhibits slightly reduced POR enzymatic activity (Agrawal 2008, Huang 2008), though it is unknown if this slight reduction is clinically significant. Due to limited information, the clinical significance of the p.Arg406His variant is uncertain at this time. References: Agrawal et al. Pharmacogenetics of P450 oxidoreductase: effect of sequence variants on activities of CYP1A2 and CYP2C19. Pharmacogenet Genomics. 2008 Jul;18(7):569-76. PMID: 18551037. Huang et al. Genetics of P450 oxidoreductase: sequence variation in 842 individuals of four ethnicities and activities of 15 missense mutations. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1733-8. PMID: 18230729. -
Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency;C2936791:Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis;C3150099:Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at