17-1650819-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_006445.4(PRPF8):c.6991G>A(p.Glu2331Lys) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRPF8 NM_006445.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• 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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a region_of_interest Required for interaction with EFTUD2 and SNRNP200 (size 34) in uniprot entity PRP8_HUMAN there are 50 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 where missense usually causes diseases, PRPF8
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869
• PP5: Variant 17-1650819-C-T is Pathogenic according to our data. Variant chr17-1650819-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 803296.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPF8	NM_006445.4	c.6991G>A	p.Glu2331Lys	missense_variant	43/43	ENST00000304992.11
PRPF8	XM_024450537.2	c.6991G>A	p.Glu2331Lys	missense_variant	43/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPF8	ENST00000304992.11	c.6991G>A	p.Glu2331Lys	missense_variant	43/43	1	NM_006445.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinitis pigmentosa 13 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.4	N;.
REVEL	Pathogenic	0.79
Sift	Uncertain	0.023	D;.
Sift4G	Uncertain	0.037	D;D
Polyphen		0.88	P;P
Vest4		0.55
MutPred		0.61		Gain of ubiquitination at E2331 (P = 0.006);Gain of ubiquitination at E2331 (P = 0.006);
MVP		0.97
MPC		0.78
ClinPred		0.97	D
GERP RS		4.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.1
Varity_R		0.96
gMVP		0.72

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: rs1597223220; hg19: chr17-1554113;