rs387906971

Positions:

• chr17-1653558-G-A

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.6353C>T​(p.Ser2118Phe) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRPF8 NM_006445.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.76

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 domain MPN (size 131) in uniprot entity PRP8_HUMAN there are 7 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 gene, where missense usually causes diseases (based on misZ statistic), PRPF8. . Gene score misZ: 8.2838 (greater than the threshold 3.09). Trascript score misZ: 11.324 (greater than threshold 3.09). The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. GenCC has associacion of the gene with neurodevelopmental disorder, retinitis pigmentosa 13, inherited retinal dystrophy, retinitis pigmentosa.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871
• PP5: Variant 17-1653558-G-A is Pathogenic according to our data. Variant chr17-1653558-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30666.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-1653558-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPF8	NM_006445.4	c.6353C>T	p.Ser2118Phe	missense_variant	39/43	ENST00000304992.11	NP_006436.3
PRPF8	XM_024450537.2	c.6353C>T	p.Ser2118Phe	missense_variant	39/43		XP_024306305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPF8	ENST00000304992.11	c.6353C>T	p.Ser2118Phe	missense_variant	39/43	1	NM_006445.4	ENSP00000304350.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Retinitis pigmentosa 13 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 02, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Pathogenic	3.7	H;H
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-4.1	D;.
REVEL	Uncertain	0.47
Sift	Benign	0.072	T;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.98	D;D
Vest4		0.87
MutPred		0.72		Loss of catalytic residue at S2118 (P = 0.0665);Loss of catalytic residue at S2118 (P = 0.0665);
MVP		0.80
MPC		2.7
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.88
gMVP		0.98

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: rs387906971; hg19: chr17-1556852;