17-1650898-G-C

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_006445.4(PRPF8):​c.6912C>G​(p.Phe2304Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

Frequency

Genomes: not found (cov: 32)

Consequence

PRPF8
NM_006445.4 missense

Scores

13
5
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.95
Variant links:
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 21 ACMG points.

PS1
Transcript NM_006445.4 (PRPF8) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
PM1
In a region_of_interest Required for interaction with EFTUD2 and SNRNP200 (size 34) in uniprot entity PRP8_HUMAN there are 30 pathogenic changes around while only 0 benign (100%) in NM_006445.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the PRPF8 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 8.2838 (above the threshold of 3.09). Trascript score misZ: 11.324 (above the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder, retinitis pigmentosa 13, inherited retinal dystrophy, retinitis pigmentosa.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 17-1650898-G-C is Pathogenic according to our data. Variant chr17-1650898-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-1650898-G-C is described in UniProt as null. Variant chr17-1650898-G-C is described in UniProt as null. Variant chr17-1650898-G-C is described in Lovd as [Pathogenic]. Variant chr17-1650898-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRPF8NM_006445.4 linkc.6912C>G p.Phe2304Leu missense_variant Exon 43 of 43 ENST00000304992.11 NP_006436.3 Q6P2Q9
PRPF8XM_024450537.2 linkc.6912C>G p.Phe2304Leu missense_variant Exon 43 of 43 XP_024306305.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRPF8ENST00000304992.11 linkc.6912C>G p.Phe2304Leu missense_variant Exon 43 of 43 1 NM_006445.4 ENSP00000304350.6 Q6P2Q9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Jan 01, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2304 of the PRPF8 protein (p.Phe2304Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 11468273, 16799052, 24938718, 28076437). This variant is also known as c.6953C>G. ClinVar contains an entry for this variant (Variation ID: 3359). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PRPF8 protein function with a positive predictive value of 80%. This variant disrupts the p.Phe2304 amino acid residue in PRPF8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 33576794; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Oct 23, 2020
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Retinitis pigmentosa 13 Pathogenic:1
Jul 15, 2001
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.53
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.97
D;D
Eigen
Uncertain
0.34
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
.;D
M_CAP
Pathogenic
0.77
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.3
M;M
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-5.0
D;.
REVEL
Pathogenic
0.87
Sift
Uncertain
0.0010
D;.
Sift4G
Uncertain
0.0020
D;D
Polyphen
0.66
P;P
Vest4
0.97
MutPred
0.97
Loss of methylation at K2302 (P = 0.1091);Loss of methylation at K2302 (P = 0.1091);
MVP
0.99
MPC
1.2
ClinPred
0.99
D
GERP RS
2.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.99
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121434240; hg19: chr17-1554192; API