rs121434242
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_004698.4(PRPF3):c.1477C>T(p.Pro493Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P493A) has been classified as Uncertain significance.
Frequency
Consequence
NM_004698.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRPF3 | NM_004698.4 | c.1477C>T | p.Pro493Ser | missense_variant | 11/16 | ENST00000324862.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRPF3 | ENST00000324862.7 | c.1477C>T | p.Pro493Ser | missense_variant | 11/16 | 1 | NM_004698.4 | P1 | |
PRPF3 | ENST00000467329.5 | n.1746C>T | non_coding_transcript_exon_variant | 8/13 | 5 | ||||
PRPF3 | ENST00000493553.1 | n.353C>T | non_coding_transcript_exon_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 10, 2020 | Published functional studies demonstrate a damaging effect with abnormal localization of the mutant P493S PRPF3 protein in photoreceptor cells (Comitato et al., 2007); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33576794, 32036094, 16799052, 21378395, 17517693, 27302685, 23647439, 11773002) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 24, 2023 | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 493 of the PRPF3 protein (p.Pro493Ser). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 11773002, 16799052, 21378395, 33576794). ClinVar contains an entry for this variant (Variation ID: 3353). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PRPF3 protein function. Experimental studies have shown that this missense change affects PRPF3 function (PMID: 17517693). For these reasons, this variant has been classified as Pathogenic. - |
Retinitis pigmentosa 18 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2002 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at