17-1673075-C-T

Variant names:

• chr17-1673075-C-T
• rs11078563
• NM_006445.4:c.3774+6G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006445.4(PRPF8):​c.3774+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,613,478 control chromosomes in the GnomAD database, including 44,357 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (9076 hom., cov: 32)
  • Exomes 𝑓: 0.21 (35281 hom.)
• Consequence: PRPF8 NM_006445.4 splice_region, intron
• Scores: Splicing: ADA: 0.00009967
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0630

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 17-1673075-C-T is Benign according to our data. Variant chr17-1673075-C-T is described in ClinVar as [Benign]. Clinvar id is 321889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRPF8	NM_006445.4	c.3774+6G>A		splice_region_variant, intron_variant	Intron 24 of 42	ENST00000304992.11	NP_006436.3
PRPF8	XM_024450537.2	c.3774+6G>A		splice_region_variant, intron_variant	Intron 24 of 42		XP_024306305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRPF8	ENST00000304992.11	c.3774+6G>A		splice_region_variant, intron_variant	Intron 24 of 42	1	NM_006445.4	ENSP00000304350.6

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45389 AN: 151990 Hom.: 9035 Cov.: 32

Gnomad AFR AF: 0.568

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.0691

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.267

GnomAD3 exomes AF: 0.207 AC: 52000 AN: 251082 Hom.: 7021 AF XY: 0.202 AC XY: 27450 AN XY: 135756

Gnomad AFR exome AF: 0.573

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.291

Gnomad EAS exome AF: 0.0702

Gnomad SAS exome AF: 0.166

Gnomad FIN exome AF: 0.191

Gnomad NFE exome AF: 0.212

Gnomad OTH exome AF: 0.216

GnomAD4 exome AF: 0.208 AC: 303346 AN: 1461372 Hom.: 35281 Cov.: 32 AF XY: 0.206 AC XY: 149958 AN XY: 727040

Gnomad4 AFR exome AF: 0.587

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.300

Gnomad4 EAS exome AF: 0.0502

Gnomad4 SAS exome AF: 0.169

Gnomad4 FIN exome AF: 0.191

Gnomad4 NFE exome AF: 0.206

Gnomad4 OTH exome AF: 0.226

GnomAD4 genome AF: 0.299 AC: 45477 AN: 152106 Hom.: 9076 Cov.: 32 AF XY: 0.291 AC XY: 21635 AN XY: 74372

Gnomad4 AFR AF: 0.568

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.303

Gnomad4 EAS AF: 0.0688

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.190

Gnomad4 NFE AF: 0.211

Gnomad4 OTH AF: 0.267

Alfa AF: 0.227 Hom.: 7852

Bravo AF: 0.308

Asia WGS AF: 0.155 AC: 539 AN: 3478

EpiCase AF: 0.217

EpiControl AF: 0.216

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Retinitis pigmentosa Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.3
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.0020
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: rs11078563; hg19: chr17-1576369; COSMIC: COSV59260837; COSMIC: COSV59260837;