rs121434241
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_004698.4(PRPF3):c.1481C>T(p.Thr494Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T494A) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004698.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRPF3 | NM_004698.4 | c.1481C>T | p.Thr494Met | missense_variant | 11/16 | ENST00000324862.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRPF3 | ENST00000324862.7 | c.1481C>T | p.Thr494Met | missense_variant | 11/16 | 1 | NM_004698.4 | P1 | |
PRPF3 | ENST00000467329.5 | n.1750C>T | non_coding_transcript_exon_variant | 8/13 | 5 | ||||
PRPF3 | ENST00000493553.1 | n.357C>T | non_coding_transcript_exon_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727236
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 494 of the PRPF3 protein (p.Thr494Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 11773002, 15085354, 20309403, 28559085). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3352). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PRPF3 function (PMID: 17932117, 20811066). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 10, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2018 | - - |
Retinitis pigmentosa Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Department of Genetics, Fundacion Jimenez Diaz University Hospital | - | Variant not found in population databases, predicted deleterious by in-silico pathogenicity predictors, and previously reported in literature (PMID: 27898983). (ACMG: PM2 Moderate, PP3 Supporting; PP5 Supporting) - |
Retinitis pigmentosa 18 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 15, 2008 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jun 23, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at