17-1650803-C-G

Position:

• chr17-1650803-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_006445.4(PRPF8):​c.7007G>C​(p.Ter2336SerextTer41) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRPF8 NM_006445.4 stop_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.02

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_006445.4 Downstream stopcodon found after 7 codons.
• PP5: Variant 17-1650803-C-G is Pathogenic according to our data. Variant chr17-1650803-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1066917.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-1650803-C-G is described in Lovd as [Pathogenic]. Variant chr17-1650803-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPF8	NM_006445.4	c.7007G>C	p.Ter2336SerextTer41	stop_lost	43/43	ENST00000304992.11
PRPF8	XM_024450537.2	c.7007G>C	p.Ter2336SerextTer41	stop_lost	43/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPF8	ENST00000304992.11	c.7007G>C	p.Ter2336SerextTer41	stop_lost	43/43	1	NM_006445.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 03, 2023

For these reasons, this variant has been classified as Pathogenic. This variant results in an extension of the PRPF8 protein. Other variant(s) that result in a similarly extended protein product (p.*2336Trpext*41) have been determined to be pathogenic (PMID: 26496393). This suggests that these extensions are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1066917). This protein extension has been observed in individuals with clinical features of retinitis pigmentosa (PMID: 31630094, 33576794; Invitae). 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 disrupts the translational stop signal of the PRPF8 mRNA. It is expected to extend the length of the PRPF8 protein by 41 additional amino acid residues. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.4
DANN	Benign	0.53
Eigen	Benign	0.13
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	N;N
Vest4		0.097
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-1554097;