19-40394181-G-C
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_181882.3(PRX):c.4171C>G(p.Arg1391Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000202 in 1,587,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. R1391W) has been classified as Uncertain significance.
Frequency
Consequence
NM_181882.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRX | NM_181882.3 | c.4171C>G | p.Arg1391Gly | missense_variant | 7/7 | ENST00000324001.8 | |
PRX | NM_001411127.1 | c.4456C>G | p.Arg1486Gly | missense_variant | 7/7 | ||
PRX | XM_017027047.2 | c.4069C>G | p.Arg1357Gly | missense_variant | 4/4 | ||
PRX | NM_020956.2 | c.*4376C>G | 3_prime_UTR_variant | 6/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRX | ENST00000324001.8 | c.4171C>G | p.Arg1391Gly | missense_variant | 7/7 | 1 | NM_181882.3 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152122Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000213 AC: 5AN: 234688Hom.: 0 AF XY: 0.0000236 AC XY: 3AN XY: 126998
GnomAD4 exome AF: 0.0000139 AC: 20AN: 1435390Hom.: 0 Cov.: 30 AF XY: 0.0000141 AC XY: 10AN XY: 710498
GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152240Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74432
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 15, 2020 | The p.R1391G variant (also known as c.4171C>G), located in coding exon 4 of the PRX gene, results from a C to G substitution at nucleotide position 4171. The arginine at codon 1391 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is not well 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 | Apr 07, 2022 | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1391 of the PRX protein (p.Arg1391Gly). This variant is present in population databases (rs369072136, gnomAD 0.03%). 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: 242185). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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