17-1673075-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• inherited retinal dystrophy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 13

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• glaucoma

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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

GnomAD2 exomes AF: 0.207 AC: 52000 AN: 251082 AF XY: 0.202

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 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

African (AFR) AF: 0.587 AC: 19653 AN: 33462

American (AMR) AF: 0.118 AC: 5299 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 7837 AN: 26134

East Asian (EAS) AF: 0.0502 AC: 1993 AN: 39700

South Asian (SAS) AF: 0.169 AC: 14566 AN: 86246

European-Finnish (FIN) AF: 0.191 AC: 10196 AN: 53406

Middle Eastern (MID) AF: 0.233 AC: 1345 AN: 5768

European-Non Finnish (NFE) AF: 0.206 AC: 228821 AN: 1111552

Other (OTH) AF: 0.226 AC: 13636 AN: 60382

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

African (AFR) AF: 0.568 AC: 23561 AN: 41456

American (AMR) AF: 0.177 AC: 2712 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1052 AN: 3468

East Asian (EAS) AF: 0.0688 AC: 357 AN: 5186

South Asian (SAS) AF: 0.154 AC: 742 AN: 4818

European-Finnish (FIN) AF: 0.190 AC: 2014 AN: 10594

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14330 AN: 67976

Other (OTH) AF: 0.267 AC: 564 AN: 2110

Alfa AF: 0.238 Hom.: 19572

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
PhyloP100		-0.063
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11078563; hg19: chr17-1576369; COSMIC: COSV59260837; COSMIC: COSV59260837;