chr17-1650818-TC-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4PP5_Very_Strong
The NM_006445.4(PRPF8):c.6991del(p.Glu2331ArgfsTer28) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
PRPF8
NM_006445.4 frameshift
NM_006445.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.92
Genes affected
PRPF8 (HGNC:17340): (pre-mRNA processing factor 8) Pre-mRNA splicing occurs in 2 sequential transesterification steps. The protein encoded by this gene is a component of both U2- and U12-dependent spliceosomes, and found to be essential for the catalytic step II in pre-mRNA splicing process. It contains several WD repeats, which function in protein-protein interactions. This protein has a sequence similarity to yeast Prp8 protein. This gene is a candidate gene for autosomal dominant retinitis pigmentosa. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 2350 codons.
PP5
?
Variant 17-1650818-TC-T is Pathogenic according to our data. Variant chr17-1650818-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 949989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-1650818-TC-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRPF8 | NM_006445.4 | c.6991del | p.Glu2331ArgfsTer28 | frameshift_variant | 43/43 | ENST00000304992.11 | |
PRPF8 | XM_024450537.2 | c.6991del | p.Glu2331ArgfsTer28 | frameshift_variant | 43/43 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRPF8 | ENST00000304992.11 | c.6991del | p.Glu2331ArgfsTer28 | frameshift_variant | 43/43 | 1 | NM_006445.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 28, 2023 | Frameshift variant predicted to result in protein truncation as the last 5 amino acids are lost and replaced with 27 incorrect amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed in large population cohorts (gnomAD); Located in the critical region required for interaction with EFTUD2 and SNRNP200 (Pena et al., 2007; Mozaffari-Jovin et al., 2013).; This variant is associated with the following publications: (PMID: 20232351, 31049658, 16799052, 29087248, 8571961, 17317632, 23704370) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change results in a frameshift in the PRPF8 gene (p.Glu2331Argfs*28). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acid(s) of the PRPF8 protein and extend the protein by 22 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 8571961, 16799052, 20232351). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 949989). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at