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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006445.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPF8	NM_006445.4	MANE Select	c.3774+6G>A		splice_region intron	N/A	NP_006436.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPF8	ENST00000304992.11	TSL:1 MANE Select	c.3774+6G>A		splice_region intron	N/A	ENSP00000304350.6
	PRPF8	ENST00000572621.5	TSL:5	c.3774+6G>A		splice_region intron	N/A	ENSP00000460348.1
	PRPF8	ENST00000883259.1		c.3774+6G>A		splice_region intron	N/A	ENSP00000553318.1

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

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;