17-1650818-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM4 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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]

ACMG classification

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

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

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

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1910994795; hg19: chr17-1554112;