Classification rationale

BA1BP4 Unclassified

PRPF8 c.1855-13C>T · exon NC_000017.10

This variant is present at high frequency in population databases, with a maximum subpopulation allele frequency of 4.59% in the African/African American population in gnomAD v4.1 (3,441/74,908 alleles, 75 homozygotes) and 4.53% in gnomAD v2.1 (1,120/24,706 alleles, 29 homozygotes), exceeding the 1% threshold for BA1 stand-alone benign classification.¹ SpliceAI predicts no significant splice impact for this intronic variant (max delta score = 0.12), providing supporting computational evidence for a benign interpretation (BP4).² This variant has been reported in ClinVar as Benign by 3 clinical laboratories (Illumina, ARUP, Labcorp/Invitae), consistent with the high population frequency and lack of splice effect.³

BA1 + BP4 → Unclassified

1 gnomad_v4 ↗gnomad_v2 ↗

2 spliceai ↗

3 clinvar ↗

Gene diagram · NM_006445.3 · variants mapped to exon structure

PRPF8 NM_006445.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 17 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

BA1 stand-alone Benign

This variant has a maximum subpopulation allele frequency of 4.59% in the African/African American population in gnomAD v4.1 (3,441/74,908 alleles, 75 homozygotes; grpmax FAF = 4.47%), and 4.53% in gnomAD v2.1 (1,120/24,706 alleles, 29 homozygotes; grpmax FAF = 4.28%). These frequencies far exceed the 1% threshold for BA1 stand-alone benign classification. The presence of 30-77 homozygotes across gnomAD versions is inconsistent with pathogenicity for a rare dominant disorder.

gnomAD v4.1 African/African American AF = 4.59% (3441/74908

gnomad_v2 ↗gnomad_v4 ↗

✓

BP4 supporting Benign

SpliceAI predicts no significant splice impact for this intronic variant (max delta score = 0.12, well below the 0.2 threshold), providing computational evidence that the variant does not disrupt splicing.

SpliceAI max delta score = 0.12 (no significant splice impact predicted)

spliceai ↗

Assessed · not applied

Pathogenic

PS2 No de novo data available for this variant in any reviewed source.

PS3 No functional studies identified for this variant in the reviewed literature.

PS4 No case-control data demonstrating enrichment of this variant in affected individuals.

PM1 Intronic variant not located in a known mutational hotspot or critical functional domain.

PM2 Present at high frequency in population databases: gnomAD v2.1 AF = 0.43% (1,217/281,232 alleles, 30 homozygotes) and gnomAD v4.1 AF = 0.24% (3,888/1,613,640 alleles, 77 homozygotes), well above the PM2 threshold of <0.1%.

PM6 No de novo reports identified for this variant in ClinVar submissions or the reviewed literature.

PP1 No segregation data available for this variant.

PP3 SpliceAI predicts no significant splice impact (max delta = 0.12, below the 0.2 threshold).

PP4 No phenotype or clinical data available for this specific variant to evaluate phenotype specificity.

PP5 ClinVar classification is Benign, not Pathogenic.

Benign

BS1 The population frequency evidence is already captured at a higher strength under BA1 (stand-alone benign).

BS2 While 30-77 homozygotes are observed in gnomAD, this evidence is already captured under BA1.

BS3 No direct functional studies have been performed on this variant.

BS4 No segregation data available to evaluate lack of segregation with disease.

BP2 No data available on observations of this variant in trans with a known pathogenic variant in PRPF8.

BP5 No alternate molecular basis for disease has been identified to explain the phenotype in individuals carrying this variant.

BP6 ClinVar classification is Benign from 3 clinical laboratories; however, the review status is 'criteria provided, single submitter' (1-star), which does not meet the 3-star expert panel threshold required for BP6 application.

N/A · 7 PVS1 · PS1 · PM5 · PP2 · BP1 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.00240946; MAF= 0.24095%, 3888/1613640 alleles, homozygotes = 77) and has highest observed frequency in the African/African American population (AF= 0.0459363; MAF= 4.59363%, 3441/74908 alleles, homozygotes = 75); grpmax FAF= 0.0446555.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.00432739; MAF= 0.43274%, 1217/281232 alleles, homozygotes = 30) and has highest observed frequency in the African/African American population (AF= 0.0453331; MAF= 4.53331%, 1120/24706 alleles, homozygotes = 29); grpmax FAF= 0.0427907.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.0029376564030029377, 54/18382 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.24% · 3888 / 1,613,640
77 hom · FAF 4.5%

African/African American 3441 / 74,908	4.6% 75 hom
Middle Eastern 18 / 6,056	0.3%
Remaining individuals 177 / 62,496	0.28% 1 hom
Admixed American 159 / 59,968	0.27%
South Asian 20 / 91,070	0.022% 1 hom
European (non-Finnish) 73 / 1,180,008	0.0062%

+ 4 not observed (European (Finnish), Amish, East Asian, Ashkenazi Jewish)

gnomAD v2.1

0.43% · 1217 / 281,232
30 hom · FAF 4.3%

African/African American 1120 / 24,706	4.5% 29 hom
Admixed American 71 / 35,358	0.2%
Remaining individuals 10 / 7,176	0.14%
South Asian 8 / 30,554	0.026% 1 hom
European (non-Finnish) 8 / 128,118	0.0062%

+ 3 not observed (Ashkenazi Jewish, East Asian, European (Finnish))

gnomAD Canada 🇨🇦

0.29% · 54 / 18,382
0 hom · FAF 3.1%

African/African American 41 / 1,018	4%
Middle Eastern 1 / 144	0.69%
Latino/Admixed American 4 / 832	0.48%
Remaining individuals 3 / 1,136	0.26%
European (non-Finnish) 5 / 11,714	0.043%

+ 4 not observed (Ashkenazi Jewish, East Asian, European (Finnish), South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

In progress — evidence not uploaded yet.

ClinVar ↗

In silico

In progress — evidence not uploaded yet.

SpliceAI ↗

Functional

In progress — evidence not uploaded yet.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

In progress — evidence not uploaded yet.

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 5 PMIDs not cited in assessment

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

26666451 ↗ In Vivo CRISPR/Cas9 Gene Editing Corrects Retinal Dystrophy in the S334ter-3 Rat Model of Autosomal Dominant Retinitis Pigmentosa. CLINVAR

20301590 ↗ Nonsyndromic Retinitis Pigmentosa Overview. CLINVAR

22234150 ↗ Clinical utility gene card for: BEST1-related dystrophies (Bestrophinopathies). CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR