NM_006445.3:c.4792G>A

PRPF8 · NP_006436.3:p.(Asp1598Asn) · NM_006445.3

GRCh37: chr17:1563289 C>T · GRCh38: chr17:1659995 C>T

Gene: PRPF8 Transcript: NM_006445.3

Final call

VUS

PS3 supporting PM2 supporting

Variant details

Gene

PRPF8

Transcript

NM_006445.3

Protein

NP_006436.3:p.(Asp1598Asn)

gnomAD AF

2.2925064778797908e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

PS3 supporting: a homologous yeast assay showed altered spliceosomal function for the D1598N-equivalent substitution.

PM2 supporting: gnomAD v4.1 allele frequency is 2.29251e-05, below the generic PM2 threshold of 0.0001.

Final determination: Under the generic ACMG/AMP 2015 fallback, two supporting criteria alone do not satisfy any pathogenic, likely pathogenic, likely benign, or benign combination, so the result is VUS.

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	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_006445.3:c.4792G>A in PRPF8 is a missense substitution predicted to produce NP_006436.3:p.(Asp1598Asn). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: the D1598 report includes a D1598N-equivalent assay but does not establish a pathogenic alternative-nucleotide variant producing p.Asp1598Asn.	PMID:24781015
PS2	Not assessed	Not assessed: no documented proband-parent genotype results establish de novo occurrence of c.4792G>A.	PMID:24781015
PS3	Met	Met, supporting: homologous Prp8-D1670N altered splicing in a controlled yeast ACT1-CUP1 reporter assay, whereas D1670H lacked the suppressor effect.	PMID:24781015
PS4	Not assessed	Not assessed: no germline case-control enrichment or affected-versus-control prevalence estimate is available for NM_006445.3:c.4792G>A.	PMID:24781015
PM1	Not assessed	Not assessed: no authoritative PRPF8 critical-domain annotation or statistically significant hotspot is available for residue 1598.
PM2	Met	Met at supporting strength: gnomAD v4.1 overall AF 2.29251e-05 is below the generic PM2 threshold of 0.0001.	gnomad_v4 gnomad_v2 generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no affected proband, second pathogenic allele, or confirmed trans phase is documented for this PRPF8 variant.
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_006445.3:c.4792G>A in PRPF8 is a missense substitution predicted to produce NP_006436.3:p.(Asp1598Asn). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: D1598 substitutions are reported, but no alternate missense change at residue 1598 is established as pathogenic for the relevant germline disorder.	PMID:24781015
PM6	Not assessed	Not assessed: no report states that c.4792G>A is apparently de novo without parental testing.	PMID:24781015
PP1	Not assessed	Not assessed: no affected-relative genotypes or informative meioses are reported for segregation analysis.
PP2	Not assessed	Not assessed: no validated PRPF8 missense constraint or gene-level pathogenic-versus-benign missense distribution is provided.
PP3	Not met	Not met: REVEL 0.638 is below the >=0.644 supporting PP3 threshold from the ClinGen SVI calibration.	revel
PP4	Not assessed	Not assessed: no patient-level phenotype or highly specific disease presentation is documented for this exact variant.	clinvar
PP5	Not met	Not met: ClinVar has zero expert-panel submissions, and both exact-variant laboratory assertions are Uncertain significance.	clinvar
BA1	Not met	Not met: the highest gnomAD v4.1 subpopulation AF is 6.75493e-05, far below the generic BA1 threshold of 0.05.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: gnomAD v4.1's highest subpopulation AF is 6.75493e-05, below the generic BS1 threshold of 0.01.	gnomad_v4 gnomad_v2
BS2	Not met	Not met: gnomAD v4.1 reports 0 homozygotes among 1,613,954 alleles, providing no homozygote evidence for BS2.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no validated assay demonstrated normal PRPF8-D1598N function, and the available yeast assay instead reported altered splicing activity.	PMID:24781015
BS4	Not assessed	Not assessed: no tested affected relatives lack the variant, so non-segregation cannot be demonstrated.
BP1	Not assessed	Not assessed: PRPF8 loss-of-function evidence does not establish a primarily truncating disease mechanism that excludes pathogenic missense variation.
BP2	Not assessed	Not assessed: no confirmed cis or trans relationship with a pathogenic variant is documented for this PRPF8 variant.
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_006445.3:c.4792G>A in PRPF8 is a missense substitution predicted to produce NP_006436.3:p.(Asp1598Asn). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.638 is above the <=0.29 supporting BP4 threshold from the ClinGen SVI calibration.	revel
BP5	Not assessed	Not assessed: no affected individual with an alternate molecular diagnosis is documented for this exact variant.	PMID:24781015
BP6	Not met	Not met: ClinVar has zero expert-panel submissions, and both exact-variant laboratory assertions are Uncertain significance.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_006445.3:c.4792G>A in PRPF8 is a missense substitution predicted to produce NP_006436.3:p.(Asp1598Asn). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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