LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-02
Case ID: NM_006445.3_c.1855-13C_T_20260802_163717
Framework: ACMG/AMP 2015
Variant classification summary

PRPF8  · NP_006436.3:p.?  · NM_006445.3
GRCh37: chr17:1581001 G>A  ·  GRCh38: chr17:1677707 G>A
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.?
gnomAD AF
0.002409459358964825 (v4.1)
ClinVar
Benign
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
This variant is present at high frequency in population databases, with a maximum subpopulation allele frequency of 4.59% in the African/African American population in gnomAD v4.1 (3,441/74,908 alleles, 75 homozygotes) and 4.53% in gnomAD v2.1 (1,120/24,706 alleles, 29 homozygotes), exceeding the 1% threshold for BA1 stand-alone benign classification.
2
SpliceAI predicts no significant splice impact for this intronic variant (max delta score = 0.12), providing supporting computational evidence for a benign interpretation (BP4).
3
This variant has been reported in ClinVar as Benign by 3 clinical laboratories (Illumina, ARUP, Labcorp/Invitae), consistent with the high population frequency and lack of splice effect.
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 Intronic variant at position c.1855-13 (intron 13) does not meet the ClinGen SVI PVS1 null-variant criteria (nonsense, frameshift, or canonical ±1,2 splice consensus). SpliceAI predicts no significant splice impact (max delta = 0.12).
spliceai pvs1_variant_assessment pvs1_gene_context
PS1 N/A Intronic variant with no predicted amino acid change; no pathogenic comparator nucleotide change at the same position can be assessed.
PS2 Not met No de novo data available for this variant in any reviewed source.
PS3 Not met No functional studies identified for this variant in the reviewed literature. SpliceAI predicts no significant splice impact (max delta = 0.12), but computational prediction alone is insufficient for PS3.
spliceai
PS4 Not met No case-control data demonstrating enrichment of this variant in affected individuals. The variant is common in population databases, inconsistent with a disease-causing role in a rare disorder.
gnomad_v2 gnomad_v4
PS5 N/A Intronic variant with no predicted amino acid change; cannot assess a different pathogenic variant at the same amino acid position.
PM1 Not met Intronic variant not located in a known mutational hotspot or critical functional domain. Cancerhotspots.org does not list this region as significant.
oncokb
PM2 Not met Present at high frequency in population databases: gnomAD v2.1 AF = 0.43% (1,217/281,232 alleles, 30 homozygotes) and gnomAD v4.1 AF = 0.24% (3,888/1,613,640 alleles, 77 homozygotes), well above the PM2 threshold of <0.1%.
gnomad_v2 gnomad_v4
PM5 N/A Intronic variant with no predicted protein change (NP_006436.3:p.?); same-residue comparator analysis cannot be performed.
pm5_candidates
PM6 Not met No de novo reports identified for this variant in ClinVar submissions or the reviewed literature.
clinvar
PP1 Not met No segregation data available for this variant.
PP2 N/A Intronic variant; PP2 applies only to missense variants in genes with a low rate of benign missense variation.
PP3 Not met SpliceAI predicts no significant splice impact (max delta = 0.12, below the 0.2 threshold). REVEL, BayesDel, and HCI prior scores are not available for this intronic variant. No computational evidence supports a pathogenic effect.
spliceai
PP4 Not met No phenotype or clinical data available for this specific variant to evaluate phenotype specificity.
PP5 Not met ClinVar classification is Benign, not Pathogenic. Additionally, the ClinVar review status is 'criteria provided, single submitter' (1-star), which does not meet the 3-star expert panel threshold required for PP5 application.
clinvar
BA1 Met This variant has a maximum subpopulation allele frequency of 4.59% in the African/African American population in gnomAD v4.1 (3,441/74,908 alleles, 75 homozygotes; grpmax FAF = 4.47%), and 4.53% in gnomAD v2.1 (1,120/24,706 alleles, 29 homozygotes; grpmax FAF = 4.28%). These frequencies far exceed the 1% threshold for BA1 stand-alone benign classification. The presence of 30-77 homozygotes across gnomAD versions is inconsistent with pathogenicity for a rare dominant disorder.
gnomad_v2 gnomad_v4
BS1 Not met The population frequency evidence is already captured at a higher strength under BA1 (stand-alone benign). Application of BS1 using the same gnomAD data would constitute double-counting of the same evidence.
gnomad_v2 gnomad_v4
BS2 Not met While 30-77 homozygotes are observed in gnomAD, this evidence is already captured under BA1. No independent healthy adult observation study beyond gnomAD population data is available.
gnomad_v2 gnomad_v4
BS3 Not met No direct functional studies have been performed on this variant. SpliceAI prediction of no effect (max delta = 0.12) is computational, not experimental, and is insufficient alone to meet BS3. The SpliceAI evidence is applied under BP4 at supporting-benign strength.
spliceai
BS4 Not met No segregation data available to evaluate lack of segregation with disease.
BP1 N/A Intronic variant; BP1 applies only to missense variants in genes where truncating variants are the primary disease mechanism.
BP2 Not met No data available on observations of this variant in trans with a known pathogenic variant in PRPF8.
BP3 N/A Intronic variant; BP3 applies to in-frame indels in repetitive regions without a known function.
BP4 Met SpliceAI predicts no significant splice impact for this intronic variant (max delta score = 0.12, well below the 0.2 threshold), providing computational evidence that the variant does not disrupt splicing.
spliceai
BP5 Not met No alternate molecular basis for disease has been identified to explain the phenotype in individuals carrying this variant.
BP6 Not met ClinVar classification is Benign from 3 clinical laboratories; however, the review status is 'criteria provided, single submitter' (1-star), which does not meet the 3-star expert panel threshold required for BP6 application.
clinvar
BP7 N/A Intronic variant; BP7 applies to synonymous variants with no predicted splice effect, not to intronic substitutions.
Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.