rs147441856
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_181882.3(PRX):c.2449C>T(p.Arg817Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R817H) has been classified as Uncertain significance.
Frequency
Consequence
NM_181882.3 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRX | NM_181882.3 | c.2449C>T | p.Arg817Cys | missense_variant | 7/7 | ENST00000324001.8 | |
PRX | NM_001411127.1 | c.2734C>T | p.Arg912Cys | missense_variant | 7/7 | ||
PRX | XM_017027047.2 | c.2347C>T | p.Arg783Cys | missense_variant | 4/4 | ||
PRX | NM_020956.2 | c.*2654C>T | 3_prime_UTR_variant | 6/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRX | ENST00000324001.8 | c.2449C>T | p.Arg817Cys | missense_variant | 7/7 | 1 | NM_181882.3 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 152188Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251086Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135758
GnomAD4 exome AF: 0.000176 AC: 258AN: 1461848Hom.: 0 Cov.: 38 AF XY: 0.000186 AC XY: 135AN XY: 727214
GnomAD4 genome ? AF: 0.000125 AC: 19AN: 152188Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7AN XY: 74336
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 14, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 29, 2021 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
PRX-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 25, 2023 | The PRX c.2449C>T variant is predicted to result in the amino acid substitution p.Arg817Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-40901810-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 24, 2022 | The p.R817C variant (also known as c.2449C>T), located in coding exon 4 of the PRX gene, results from a C to T substitution at nucleotide position 2449. The arginine at codon 817 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Charcot-Marie-Tooth disease type 4F Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Charcot-Marie-Tooth disease type 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 817 of the PRX protein (p.Arg817Cys). This variant is present in population databases (rs147441856, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PRX-related conditions. ClinVar contains an entry for this variant (Variation ID: 245733). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at