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PRPF8c.4775A>CUncertain significance
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Variant interpretation report

PRPF8 c.4775A>C, p.(Asp1592Ala)

NM_006445.3:c.4775A>C NP_006436.3:p.(Asp1592Ala) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About PRPF8

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting

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.

PP3Supporting
PP3 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 2 met · 20 not met · 0 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

Met · 2

PM2 SupportingAbsent 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes).
  • Absent from gnomAD v4.1 (genomes + exomes).
  • Absent from gnomAD-Canada v1.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP3 SupportingREVEL 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. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.909 (pathogenic prediction).
  • BayesDel score: 0.384561.
  • SpliceAI max delta: 0.02 (no splicing impact).
Sources
revelbayesdelspliceai ↗

Not met · 20 · evaluated, threshold not reached

PS1 No established pathogenic variant at the same amino acid position (p.Asp1592) with a different nucleotide change. This variant is entirely absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no pathogenic comparator at codon 1592.
Still missing
  • No ClinVar data for PRPF8 codon 1592.
Sources
clinvar ↗
PS2 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. Details ▾Hide ▴
Evidence considered
  • PMID:38976971 reports a de novo PRPF8 stop-gain variant at codon 1850
  • not at codon 1592.
Still missing
  • No de novo testing data for this variant.
PS3 No functional data exists for this variant. No experimental studies in literature, COSMIC, or OncoKB. No systematically characterized range encompassing p.Asp1592. Details ▾Hide ▴
Evidence considered
  • OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence.
  • Absent from COSMIC somatic database.
Still missing
  • No in vitro or in vivo functional data for p.Asp1592Ala.
Sources
oncokb ↗
PS4 No case-control or clinical cohort data available. Variant is absent from ClinVar and has no published clinical observations. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no case-control or prevalence data identified.
Still missing
  • No clinical cohort data in literature or databases.
Sources
clinvar ↗
PM1 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. Details ▾Hide ▴
Evidence considered
  • Not in a cancerhotspots.org significant hotspot. No domain-level pathogenic enrichment data identified.
Still missing
  • No domain-level pathogenic enrichment data for p.Asp1592.
PM5 No same-residue comparator variant (p.Asp1592) classified as pathogenic identified in ClinVar. Automated PM5 candidate search returned no candidates. Details ▾Hide ▴
Evidence considered
  • PM5 pipeline found 0 same-residue candidates at p.Asp1592.
Still missing
  • No pathogenic comparator variants at codon 1592.
Sources
pm5_candidatesclinvar ↗
PM6 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. Details ▾Hide ▴
Evidence considered
  • PMID:38976971 reports de novo PRPF8 c.5548C>T p.(Arg1850*)
  • not c.4775A>C.
Still missing
  • No de novo testing for c.4775A>C specifically.
PP1 No cosegregation data available. No family studies or linkage analysis for this variant. Details ▾Hide ▴
Evidence considered
  • No cosegregation or family studies identified.
Still missing
  • No family or segregation data.
PP2 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. Details ▾Hide ▴
Evidence considered
  • No missense constraint data (Z-score) available for PRPF8.
Still missing
  • PRPF8 missense Z-score not computed in evidence pipeline.
PP4 No patient phenotype or clinical data specific to this variant. The variant has not been observed in any clinical cohort. Details ▾Hide ▴
Evidence considered
  • No clinical phenotype data available for this variant.
Still missing
  • No phenotype or clinical context for c.4775A>C.
BA1 Absent from gnomAD. BA1 requires allele frequency >1% in any population. The variant has zero observations across all population databases. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 Absent from gnomAD. BS1 requires allele frequency >0.3% in population databases. The variant has zero observations. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD
  • no observation in healthy controls.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB reports Unknown Oncogenic Effect with no variant-specific functional data.
Still missing
  • No functional studies for this variant.
Sources
oncokb ↗
BS4 No segregation data available to demonstrate lack of cosegregation with disease. No family studies exist for this variant. Details ▾Hide ▴
Evidence considered
  • No cosegregation or family data available.
Still missing
  • No family/segregation data.
BP1 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. Details ▾Hide ▴
Evidence considered
  • PRPF8 harbors known pathogenic missense variants (e.g.
  • p.Tyr2334Asn in RP).
BP2 No observation of this variant in trans with a known pathogenic PRPF8 variant. Variant absent from all population and clinical databases. Details ▾Hide ▴
Evidence considered
  • No trans configuration data available.
Still missing
  • No observation in trans.
BP4 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.909 (pathogenic prediction
  • contradicts BP4).
  • BayesDel: 0.384561.
Sources
revelbayesdel
BP5 No cases identified where this variant was found in an individual with an alternate molecular basis for disease. No clinical case data exists. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis cases identified.
Still missing
  • No clinical case reports.
PS5 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. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no comparator pathogenic variant at codon 1592.
Still missing
  • No ClinVar data for PRPF8 codon 1592.
Sources
clinvar ↗
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense 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. Details ▾Hide ▴
Evidence considered
  • Missense substitution at c.4775A>C
  • variant bucket 'other' per PVS1 decision tree.
Sources
pvs1_generic_framework ↗
PP5 N/AVariant 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. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar.
Sources
clinvar ↗
BP6 N/AVariant is absent from ClinVar. BP6 requires a reputable source to have classified this variant as benign. No classification exists. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar.
Sources
clinvar ↗
BP7 N/ANot 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). Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 applies only to synonymous variants.

Identifiers

Gene
PRPF8
Transcript
NM_006445.3
Coding (HGVS c.)
NM_006445.3:c.4775A>C
Protein (HGVS p.)
NP_006436.3:p.(Asp1592Ala)
GRCh38
chr17:1660442 T>G
GRCh37
chr17:1563736 T>G

Gene diagram

Every interpreted variant in PRPF8, mapped onto the exon structure of NM_006445.3. Select a row to find it on the plot.

PRPF8NM_006445.3
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +49 bp
0.020
SpliceAI acceptor gainat +381 bp
0.000
SpliceAI donor lossat -10 bp
0.000
SpliceAI donor gainat -5 bp
0.000
Pangolin splice lossmagnitude shown
-0.020
Pangolin splice gain
0.000

Other predictors

REVEL
0.909
BayesDel
0.385

How the predictions were used

PP3 SupportingREVEL 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. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.909 (pathogenic prediction).
  • BayesDel score: 0.384561.
  • SpliceAI max delta: 0.02 (no splicing impact).
Sources
revelbayesdelspliceai ↗
BP4 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.909 (pathogenic prediction
  • contradicts BP4).
  • BayesDel: 0.384561.
Sources
revelbayesdel
BP7 N/ANot 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). Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 applies only to synonymous variants.

Statement

In silico

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

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from 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.

Functional

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.

Somatic

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.