Applied · 6

Strength Supporting Moderate Strong Very strong

✓

BA1 stand-alone Benign

This variant has a maximum credible population allele frequency of 4.58% in gnomAD v2.1 (grpmax FAF=0.0458484) and 4.76% in gnomAD v4.1 (grpmax FAF=0.0476449), well above the 1% BA1 threshold. Observed in 32 homozygotes in v2.1 and 89 homozygotes in v4.1, which is incompatible with a rare autosomal dominant disorder.

gnomAD v2.1: grpmax FAF=4.58%1327/282876 alleles32 homozygotes

gnomad_v2 ↗gnomad_v4 ↗

✓

BS1 supporting Benign

This variant has a global allele frequency of 0.47% in gnomAD v2.1 and 0.27% in v4.1, exceeding the BS1 threshold of >0.3%. The frequency is far greater than expected for PRPF8-associated autosomal dominant retinitis pigmentosa. (Note: BA1 at stand-alone benign level subsumes this evidence.)

gnomAD v2.1 global AF=0.47% (>0.3% BS1 threshold)gnomAD v4.1 global AF=0.27%Frequency incompatible with rare Mendelian disorder prevalence

gnomad_v2 ↗gnomad_v4 ↗

✓

BS2 strong Benign

This variant has been observed in the homozygous state in 32 individuals in gnomAD v2.1 and 89 individuals in gnomAD v4.1. Given that PRPF8-associated disease (retinitis pigmentosa) is autosomal dominant with full penetrance, the presence of numerous healthy homozygotes in population databases constitutes strong evidence for a benign classification.

gnomAD v2.1: 32 homozygotes (31 in African/African American subpopulation)gnomAD v4.1: 89 homozygotes (86 in African/African American subpopulation)PRPF8-associated retinitis pigmentosa is autosomal dominant

gnomad_v2 ↗gnomad_v4 ↗

✓

BP4 supporting Benign

SpliceAI predicts no splicing impact for this synonymous variant (max delta score=0.01), supporting a lack of functional consequence. REVEL and BayesDel scores are not available for this variant.

SpliceAI max delta = 0.01 (no predicted donor gaindonor lossacceptor gain

spliceai ↗

✓

BP6 supporting Benign

This variant has been classified as Benign by 3 independent clinical laboratories in ClinVar (Illumina, ARUP Laboratories, Labcorp/Invitae; ClinVar ID 321876). Although the aggregate review status is 1-star ('criteria provided, single submitter'), the concordant benign classification from multiple clinical testing laboratories provides supporting evidence for a benign interpretation.

ClinVar classification: Benign (ClinVar ID 321876)3 clinical laboratories: IlluminaARUP Laboratories

clinvar ↗

✓

BP7 supporting Benign

This is a synonymous variant (p.Leu2083=) with no predicted impact on splicing. SpliceAI analysis yields a max delta score of 0.01, indicating no creation or disruption of splice sites. These findings are consistent with a neutral effect, satisfying BP7.

Synonymous variant (c.6247C>Tp.Leu2083=)SpliceAI max delta = 0.01: no predicted donor/acceptor gain or loss

spliceai ↗

Assessed · not applied

Pathogenic

PS2 No de novo observation with confirmed maternity and paternity has been reported for this variant.

PS3 No functional studies testing this specific variant or a systematically characterized range including position 6247 were identified in the reviewed literature.

PS4 No case-control data demonstrating enrichment in affected individuals; the variant is common in population databases (gnomAD v2.1 AF=0.47%, 32 homozygotes), inconsistent with prevalence of PRPF8-associated retinitis pigmentosa.

PM2 This variant is present in gnomAD at high frequency: v2.1 AF=0.47% (1327/282876 alleles, 32 homozygotes), v4.1 AF=0.27% (4309/1614142 alleles, 89 homozygotes).

PM6 No de novo observation (with or without confirmed parentage) has been reported for this variant.

PP1 No co-segregation data are available for this variant.

PP3 REVEL and BayesDel scores are unavailable for this variant; SpliceAI predicts no splicing impact (max delta=0.01).

PP4 No patient phenotype or family history data were provided for this case; PP4 cannot be assessed.

PP5 ClinVar reports this variant as Benign from 3 clinical laboratories (ClinVar ID 321876).

Benign

BS3 No well-established functional studies demonstrating a lack of damaging effect were identified for this variant in the reviewed literature.

BS4 No segregation data are available to assess lack of co-segregation with disease.

BP2 No data on observation in trans with a known pathogenic variant are available.

BP5 No evidence that this variant is found in a case with an alternate molecular basis for disease.

N/A · 7 PVS1 · PS1 · PM1 · PM5 · PP2 · BP1 · BP3

African/African American 3673 / 75,010	4.9% 86 hom
Middle Eastern 21 / 6,062	0.35%
Admixed American 197 / 60,008	0.33%
Remaining individuals 201 / 62,510	0.32% 2 hom
South Asian 24 / 91,082	0.026% 1 hom
European (non-Finnish) 192 / 1,180,036	0.016%
East Asian 1 / 44,878	0.0022%

African/African American 1199 / 24,960	4.8% 31 hom
Admixed American 88 / 35,440	0.25%
Remaining individuals 11 / 7,228	0.15%
South Asian 9 / 30,616	0.029% 1 hom
European (non-Finnish) 20 / 129,192	0.015%

African/African American 41 / 1,020	4%
Middle Eastern 1 / 144	0.69%
Latino/Admixed American 4 / 838	0.48%
Remaining individuals 3 / 1,138	0.26%
European (non-Finnish) 6 / 11,738	0.051%