Variant 17-1650819-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 5.92

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:

PRPF8 (HGNC:):

PRPF8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 30 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). GenCC has associacion of gene with neurodevelopmental disorder, retinitis pigmentosa 13, inherited retinal dystrophy, retinitis pigmentosa.

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: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPF8	NM_006445.4 linkuse as main transcript	c.6991G>A	p.Glu2331Lys	missense_variant	43/43	ENST00000304992.11	NP_006436.3	Q6P2Q9
PRPF8	XM_024450537.2 linkuse as main transcript	c.6991G>A	p.Glu2331Lys	missense_variant	43/43		XP_024306305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPF8	ENST00000304992.11 linkuse as main transcript	c.6991G>A	p.Glu2331Lys	missense_variant	43/43	1	NM_006445.4	ENSP00000304350.6		Q6P2Q9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

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

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

D;D

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

.;D

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

3.1

M;M

PrimateAI

Pathogenic

0.86

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

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

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