NM_006445.3:c.4775A>C

PRPF8 · NP_006436.3:p.(Asp1592Ala) · NM_006445.3

GRCh37: chr17:1563736 T>G · GRCh38: chr17:1660442 T>G

Gene: PRPF8 Transcript: NM_006445.3

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

PRPF8

Transcript

NM_006445.3

Protein

NP_006436.3:p.(Asp1592Ala)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

In silico analysis with REVEL (score: 0.909) predicts a pathogenic effect, meeting PP3 at supporting strength.

The variant is absent from ClinVar, COSMIC, and cancerhotspots.org, and no published literature mentions this specific variant.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Missense variant p.(Asp1592Ala); PVS1 requires null variants (nonsense, frameshift, or canonical splice ±1,2). Per ClinGen SVI PVS1 framework (PMC6185798), this variant does not qualify for any PVS1 strength level.	pvs1_generic_framework
PS1	Not met	No established pathogenic variant at the same amino acid position (p.Asp1592) with a different nucleotide change. This variant is entirely absent from ClinVar.	clinvar
PS2	Not met	No de novo observation of this variant. One de novo PRPF8 variant reported at a different position (c.5548C>T, p.Arg1850*) is not relevant to this variant.
PS3	Not met	No functional data exists for this variant. No experimental studies in literature, COSMIC, or OncoKB. No systematically characterized range encompassing p.Asp1592.	oncokb
PS4	Not met	No case-control or clinical cohort data available. Variant is absent from ClinVar and has no published clinical observations.	clinvar
PS5	Not met	No different pathogenic missense variant identified at codon 1592 in ClinVar or literature. PS5 requires an established pathogenic variant at the same residue with a different amino acid change.	clinvar
PM1	Not met	Variant p.Asp1592 is not located in a statistically significant hotspot per cancerhotspots.org. No evidence from literature that this residue lies within a well-characterized critical functional domain with established pathogenic enrichment.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No same-residue comparator variant (p.Asp1592) classified as pathogenic identified in ClinVar. Automated PM5 candidate search returned no candidates.	pm5_candidates clinvar
PM6	Not met	No de novo observation of this specific variant. While a de novo PRPF8 variant has been reported (PMID:38976971, c.5548C>T p.Arg1850*), it is at a different position and provides no evidence for NM_006445.3:c.4775A>C.
PP1	Not met	No cosegregation data available. No family studies or linkage analysis for this variant.
PP2	Not met	PP2 requires a gene with a low rate of benign missense variation and where missense variants are a common disease mechanism. Without gnomAD constraint metrics (Z-score) for PRPF8 missense variation in the evidence, PP2 cannot be confidently applied. REVEL score of 0.909 suggests deleterious effect but does not substitute for gene-level missense constraint data.
PP3	Met	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 bayesdel spliceai
PP4	Not met	No patient phenotype or clinical data specific to this variant. The variant has not been observed in any clinical cohort.
PP5	N/A	Variant is absent from ClinVar. PP5 requires a reputable source (e.g., ClinVar expert panel) to have classified this variant as pathogenic. No classification exists to evaluate.	clinvar
BA1	Not met	Absent from gnomAD. BA1 requires allele frequency >1% in any population. The variant has zero observations across all population databases.	gnomad_v2 gnomad_v4
BS1	Not met	Absent from gnomAD. BS1 requires allele frequency >0.3% in population databases. The variant has zero observations.	gnomad_v2 gnomad_v4
BS2	Not met	No observation in healthy adults. The variant is absent from all population databases with no evidence of occurrence in trans with a pathogenic variant or in controls.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate no deleterious effect for this variant. No functional data of any kind exists for p.Asp1592Ala.	oncokb
BS4	Not met	No segregation data available to demonstrate lack of cosegregation with disease. No family studies exist for this variant.
BP1	Not met	PRPF8 has documented pathogenic missense variants in addition to truncating variants (e.g., p.Tyr2334Asn associated with retinitis pigmentosa). BP1 requires the gene to be associated primarily with truncating variants causing disease.
BP2	Not met	No observation of this variant in trans with a known pathogenic PRPF8 variant. Variant absent from all population and clinical databases.
BP4	Not met	REVEL score of 0.909 strongly predicts a deleterious effect. BP4 requires multiple lines of computational evidence suggesting no impact on the gene product, which is contradicted by the high REVEL score.	revel bayesdel
BP5	Not met	No cases identified where this variant was found in an individual with an alternate molecular basis for disease. No clinical case data exists.
BP6	N/A	Variant is absent from ClinVar. BP6 requires a reputable source to have classified this variant as benign. No classification exists.	clinvar
BP7	N/A	Not a synonymous (silent) variant. BP7 is specific to synonymous variants with no predicted splice impact. NM_006445.3:c.4775A>C is a missense substitution p.(Asp1592Ala).

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