17-1650898-G-C

Variant names:

• chr17-1650898-G-C
• rs121434240
• NM_006445.4:c.6912C>G

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1 PM1 PM2 PP2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.95

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 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
PRPF8	NM_006445.4	c.6912C>G	p.Phe2304Leu	missense_variant	Exon 43 of 43	ENST00000304992.11	NP_006436.3
PRPF8	XM_024450537.2	c.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
PRPF8	ENST00000304992.11	c.6912C>G	p.Phe2304Leu	missense_variant	Exon 43 of 43	1	NM_006445.4	ENSP00000304350.6

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

Submissions by phenotype

not provided Pathogenic:2

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

- -

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. -

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

Other links and lift over

dbSNP: rs121434240; hg19: chr17-1554192;