LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-02
Case ID: NM_006445.3_c.2631G_A_20260802_163814
Framework: ACMG/AMP 2015
Variant classification summary

PRPF8  · NP_006436.3:p.(Ala877=)  · NM_006445.3
GRCh37: chr17:1579270 C>T  ·  GRCh38: chr17:1675976 C>T
Gene: PRPF8 Transcript: NM_006445.3
Final call
All criteria require review: For research and educational purposes only.
Variant details
Gene
PRPF8
Transcript
NM_006445.3
Protein
NP_006436.3:p.(Ala877=)
gnomAD AF
0.002499349450440515 (v4.1)
ClinVar
Benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_006445.3:c.2631G>A (p.Ala877=) is a synonymous variant in PRPF8.
2
This variant is present at high frequency in population databases, with an allele frequency of 4.68% in the African/African American population in gnomAD v2.1 (1168/24946 alleles, 32 homozygotes) and 4.75% in gnomAD v4.1 (3561/75022 alleles, 84 homozygotes), meeting BA1 (stand-alone benign).
3
The variant is observed in the homozygous state in 33 individuals in gnomAD v2.1 and 86 individuals in gnomAD v4.1, consistent with a benign polymorphism (BS2_Supporting).
4
ClinVar classifies this variant as Benign with 2-star review status ('criteria provided, multiple submitters, no conflicts'; Variation ID: 321901), meeting BP6 (Supporting).
5
SpliceAI predicts no splice impact (max delta = 0.00), meeting BP4 (Supporting) and BP7 (Supporting) for this synonymous variant.
6
No pathogenic criteria are met. The combined benign evidence (BA1, BS2_Supporting, BP4_Supporting, BP6_Supporting, BP7_Supporting) strongly supports a Benign classification.
Final determination:
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 Synonymous variant (p.Ala877=) not predicted to result in a null effect; PVS1 applies only to nonsense, frameshift, and canonical splice site variants.
pvs1_generic_framework pvs1_variant_assessment
PS1 N/A Synonymous variant produces no amino acid change; PS1 requires a different nucleotide change producing the same amino acid change previously established as pathogenic.
PS2 Not met No de novo occurrence data available for this variant with confirmed maternity and paternity.
PS3 Not met No variant-specific functional studies or systematic range characterization identified for this synonymous variant.
PS4 Not met No case-control or variant enrichment data in affected individuals available.
PS5 Not met This variant has not been reported as pathogenic in multiple affected probands; ClinVar classification is Benign.
clinvar
PM1 Not met Not located in a statistically significant mutational hotspot (cancerhotspots.org) and no evidence of location in a well-established functional domain without benign variation.
PM2 Not met Present at high frequency in population databases (gnomAD global AF 0.45%; AFR AF 4.68%), far exceeding the <0.1% threshold required for PM2 application.
gnomad_v2 gnomad_v4
PM5 N/A Synonymous variant (p.Ala877=); PM5 requires a different pathogenic missense change at the same amino acid residue.
pm5_candidates
PM6 Not met No de novo reports for this variant (with or without confirmed maternity/paternity).
PP1 Not met No cosegregation data available in affected families.
PP2 N/A Synonymous variant, not a missense change; PP2 applies to missense variants in genes with a low rate of benign missense variation.
PP3 Not met SpliceAI predicts no splice impact (max delta = 0.00); REVEL and BayesDel scores are not available for this synonymous variant; no computational evidence supports a pathogenic effect.
spliceai
PP4 Not met No proband phenotype data provided; cannot assess specificity of patient phenotype for PRPF8-associated disease.
PP5 Not met ClinVar classifies this variant as Benign (Variation ID: 321901), not Pathogenic. PP5 requires a reputable source to report the variant as pathogenic.
clinvar
BA1 Met Allele frequency exceeds 1% in the African/African American population (AFR AF 4.68% in gnomAD v2.1, 4.75% in gnomAD v4.1). Observed in 33 homozygous individuals in v2.1 and 86 in v4.1. This variant is a common population polymorphism.
gnomad_v2 gnomad_v4
BS1 N/A Population frequency evidence is fully accounted for by BA1 (allele frequency exceeds the 1% stand-alone benign threshold); BS1 is superseded.
gnomad_v2 gnomad_v4
BS2 Met Observed in the homozygous state in 33 individuals in gnomAD v2.1 and 86 individuals in gnomAD v4.1, presumed healthy population controls. Homozygous observation in a dominantly inherited disorder (RP13) is inconsistent with pathogenicity.
gnomad_v2 gnomad_v4
BS3 Not met No well-established functional studies demonstrate a lack of damaging effect for this variant.
BS4 Not met No segregation data available in affected families to assess lack of cosegregation with disease.
BP1 N/A Synonymous variant, not a missense change; BP1 applies to missense variants in genes where only truncating variants are known to cause disease.
BP2 Not met No data available on observation of this variant in trans with a known pathogenic variant.
BP3 N/A Not an in-frame deletion or insertion; this is a single-nucleotide synonymous substitution.
BP4 Met SpliceAI predicts no splice impact (max delta = 0.00). As a synonymous variant with no predicted cryptic splice site creation or native splice site disruption, multiple lines of computational evidence support a benign interpretation.
spliceai
BP5 Not met No observation of this variant in cases where an alternate molecular basis for disease has been identified.
BP6 Met ClinVar classifies this variant as Benign (Variation ID: 321901) with review status 'criteria provided, multiple submitters, no conflicts' (2-star). A reputable source consistently reports this variant as benign.
clinvar
BP7 Met Synonymous variant (p.Ala877=) with SpliceAI predicting no impact on splicing (max delta = 0.00). The high population frequency (AFR AF 4.7%) also indicates this nucleotide position is not highly conserved. All conditions for BP7 are satisfied.
spliceai gnomad_v2 gnomad_v4
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