17-1650884-T-C

Variant names:

• chr17-1650884-T-C
• rs121434236
• NM_006445.4:c.6926A>G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_006445.4(PRPF8):​c.6926A>G​(p.His2309Arg) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H2309P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRPF8 NM_006445.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.73

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 19 ACMG points.

• PM1: In a helix (size 2) in uniprot entity PRP8_HUMAN there are 9 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 chr17-1650884-T-G is described in Lovd as [Likely_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, 0.989
• PP5: Variant 17-1650884-T-C is Pathogenic according to our data. Variant chr17-1650884-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 3355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-1650884-T-C is described in UniProt as null. Variant chr17-1650884-T-C is described in UniProt as null. Variant chr17-1650884-T-C is described in Lovd as [Pathogenic]. Variant chr17-1650884-T-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.6926A>G	p.His2309Arg	missense_variant	Exon 43 of 43	ENST00000304992.11	NP_006436.3
PRPF8	XM_024450537.2	c.6926A>G	p.His2309Arg	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.6926A>G	p.His2309Arg	missense_variant	Exon 43 of 43	1	NM_006445.4	ENSP00000304350.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 13 Pathogenic:1

Jul 15, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Feb 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 2309 of the PRPF8 protein (p.His2309Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 18695108). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3355). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PRPF8 function (PMID: 28515276). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy Pathogenic:1

Apr 03, 2017

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	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.1	D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.73
MutPred		0.96		Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);
MVP		0.98
MPC		1.4
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs121434236; hg19: chr17-1554178;