Classification rationale

PM2PP3 VUS

PRPF8 c.4775A>C

NM_006445.3:c.4775A>C (p.Asp1592Ala) in PRPF8 is a missense variant absent from gnomAD v2.1 and v4.1 population databases, meeting PM2 at supporting strength.¹ In silico analysis with REVEL (score: 0.909) predicts a pathogenic effect, meeting PP3 at supporting strength.² The variant is absent from ClinVar, COSMIC, and cancerhotspots.org, and no published literature mentions this specific variant.³ No functional data, de novo observations, segregation data, or clinical case reports exist for this variant, leaving PVS1, PS1-PS5, PM1, PM5-PM6, PP1-PP2, PP4-PP5, and all benign criteria not met or not applicable.

PM2 + PP3 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗

2 revel

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 · 19 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Absent from gnomAD v2.1 and v4.1 population databases, meeting the PM2 threshold of <0.1% allele frequency. The variant has not been observed in large population cohorts.

Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (genomes + exomes).Absent from gnomAD-Canada v1.0.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

PP3 supporting Pathogenic

REVEL score of 0.909 predicts a pathogenic effect. Multiple in silico tools support a deleterious impact of this missense substitution. SpliceAI max delta 0.02 indicates no splicing effect, consistent with a missense mechanism.

REVEL score: 0.909 (pathogenic prediction).BayesDel score: 0.384561.SpliceAI max delta: 0.02 (no splicing impact).

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No established pathogenic variant at the same amino acid position (p.Asp1592) with a different nucleotide change.

PS2 No de novo observation of this variant.

PS3 No functional data exists for this variant.

PS4 No case-control or clinical cohort data available.

PM1 Variant p.Asp1592 is not located in a statistically significant hotspot per cancerhotspots.org.

PM5 No same-residue comparator variant (p.Asp1592) classified as pathogenic identified in ClinVar.

PM6 No de novo observation of this specific variant.

PP1 No cosegregation data available.

PP2 PP2 requires a gene with a low rate of benign missense variation and where missense variants are a common disease mechanism.

PP4 No patient phenotype or clinical data specific to this variant.

Benign

BA1 Absent from gnomAD.

BS1 Absent from gnomAD.

BS2 No observation in healthy adults.

BS3 No well-established in vitro or in vivo functional studies demonstrate no deleterious effect for this variant.

BS4 No segregation data available to demonstrate lack of cosegregation with disease.

BP1 PRPF8 has documented pathogenic missense variants in addition to truncating variants (e.g., p.Tyr2334Asn associated with retinitis pigmentosa).

BP2 No observation of this variant in trans with a known pathogenic PRPF8 variant.

BP4 REVEL score of 0.909 strongly predicts a deleterious effect.

BP5 No cases identified where this variant was found in an individual with an alternate molecular basis for disease.

N/A · 4 PVS1 · PP5 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.909. BayesDel score = 0.384561.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PRPF8, a core component of spliceosome complexes, is infrequently altered in cancer.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots