rs121434239

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_006445.4(PRPF8):c.6901C>T(p.Pro2301Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2301L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

PRPF8
NM_006445.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.68

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]

PRPF8 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-1650908-G-A is described in Lovd as [Pathogenic].

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, 0.994

PP5

Variant 17-1650909-G-A is Pathogenic according to our data. Variant chr17-1650909-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 867220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-1650909-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRPF8	NM_006445.4 link	c.6901C>T	p.Pro2301Ser	missense_variant	Exon 43 of 43	ENST00000304992.11	NP_006436.3	Q6P2Q9
PRPF8	XM_024450537.2 link	c.6901C>T	p.Pro2301Ser	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 link	c.6901C>T	p.Pro2301Ser	missense_variant	Exon 43 of 43	1	NM_006445.4	ENSP00000304350.6		Q6P2Q9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

May 13, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30572641, 38234607, 23704370, 17317632, 23950152, 36460718, 15994872, 37510321, 17061239) -

Dec 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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 PRPF8 protein function. ClinVar contains an entry for this variant (Variation ID: 867220). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 17061239, 23950152). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2301 of the PRPF8 protein (p.Pro2301Ser). -

Retinal dystrophy

Pathogenic:2

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 09, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

.;D

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;M

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-7.2

D;.

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.95

MutPred

0.94

Loss of methylation at K2302 (P = 0.1033);Loss of methylation at K2302 (P = 0.1033);

MVP

0.99

MPC

1.3

ClinPred

1.0

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over