LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-02
Case ID: NM_006445.3_c.6247C_T_20260802_164313
Framework: ACMG/AMP 2015
Variant classification summary

PRPF8  · NP_006436.3:p.(Leu2083=)  · NM_006445.3
GRCh37: chr17:1556958 G>A  ·  GRCh38: chr17:1653664 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.(Leu2083=)
gnomAD AF
0.0026695296944135027 (v4.1)
ClinVar
Benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_006445.3:c.6247C>T (p.Leu2083=) is a synonymous variant in PRPF8 with an allele frequency of 4.8% in the African/African American population in gnomAD (31–86 homozygotes observed), far exceeding the BA1 stand-alone benign threshold (>1%).
2
The overall population allele frequency (0.47% in gnomAD v2.1, 0.27% in v4.1) exceeds the BS1 threshold (>0.3%), providing strong evidence against pathogenicity.
3
The variant has been observed in the homozygous state in 32 (v2.1) and 89 (v4.1) healthy individuals in gnomAD, satisfying BS2 at strong strength.
4
SpliceAI predicts no significant splice impact (max delta 0.01) and the variant is synonymous (p.Leu2083=), supporting a benign interpretation under BP4 and BP7.
5
This variant has been reported in ClinVar as Benign by 3 independent clinical laboratories (VariationID 321876), providing additional supporting evidence under BP6.
6
Applying ACMG/AMP 2015 combination rules: BA1 (stand-alone) alone is sufficient for a Benign classification. The cumulative weight of BA1 + BS1 (strong) + BS2 (strong) + BP4 (supporting) + BP6 (supporting) + BP7 (supporting) provides overwhelming evidence of 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 This is a synonymous variant (NM_006445.3:c.6247C>T; NP_006436.3:p.(Leu2083=)) and does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). The pvs1_variant_assessment confirms variant_bucket='other' and apply_generic_pvs1_framework=false.
pvs1_variant_assessment pvs1_gene_context
PS1 N/A PS1 requires a different nucleotide change at the same codon producing the same missense amino acid change. This is a synonymous variant (p.Leu2083=) with no amino acid alteration; PS1 does not apply.
PS2 Not met PS2 requires a confirmed de novo observation (both maternity and paternity confirmed) in a patient with disease and no family history. No de novo report for NM_006445.3:c.6247C>T was identified in ClinVar submissions or the literature.
PS3 Not met PS3 requires well-established in vitro or in vivo functional studies demonstrating a damaging effect. No functional studies testing NM_006445.3:c.6247C>T were identified. The variant is synonymous and no experimental functional data exists for this variant or a systematically characterized range that includes it.
PS4 Not met PS4 requires the prevalence of the variant in affected individuals to be significantly increased compared to controls. This variant is common in the general population (gnomAD overall AF=0.47% in v2.1, 0.27% in v4.1; African population AF=4.8% with 86–89 homozygotes). Its high population frequency is inconsistent with a requirement for enrichment in affected individuals. No case-control study demonstrating enrichment was identified.
gnomad_v2 gnomad_v4
PS5 Not met PS5 requires a reputable source to have recently classified this variant as pathogenic. ClinVar classifies this variant as Benign (VariationID 321876), not pathogenic. No reputable source reports it as pathogenic.
clinvar
PM1 Not met PM1 requires the variant to be located in a mutational hotspot or critical, well-established functional domain without benign variation. The variant is at position p.Leu2083. The cancerhotspots.org database indicates this residue is not a statistically significant hotspot (residue_significant=false). No domain-level evidence was identified that specifically implicates this synonymous position as a critical functional domain where benign variation is absent. The adjacent region is tolerant of variation as demonstrated by the high population frequency.
PM2 Not met PM2 requires absence from (or very low frequency in) population databases (<0.1% for non-VCEP). This variant is present in gnomAD at AF=0.47% (v2.1) and AF=0.27% (v4.1), both well above the 0.1% threshold. PM2 is not met.
gnomad_v2 gnomad_v4
PM5 N/A PM5 requires a different pathogenic missense variant at the same amino acid residue. This is a synonymous variant (p.Leu2083=) — there is no amino acid change, so PM5 comparator semantics do not apply. pm5_candidates.json confirms eligible_for_classic_pm5_search=false.
pm5_candidates
PM6 Not met PM6 requires a de novo observation without confirmation of paternity and maternity. No de novo report for NM_006445.3:c.6247C>T was identified in any reviewed source.
PP1 Not met PP1 requires cosegregation with disease in multiple affected family members. No segregation data was identified for NM_006445.3:c.6247C>T.
PP2 N/A PP2 applies to missense variants in genes with a low rate of benign missense variation and where missense variants are a common mechanism of disease. NM_006445.3:c.6247C>T is a synonymous variant (p.Leu2083=), not a missense variant. PP2 does not apply.
PP3 Not met PP3 requires multiple lines of computational evidence supporting a deleterious effect. SpliceAI predicts no significant splice impact (max delta score 0.01). REVEL and BayesDel scores are not available (synonymous variant). No in silico tool predicts a deleterious effect for this synonymous substitution.
spliceai
PP4 Not assessed PP4 requires the patient's phenotype or family history to be highly specific for the gene. No patient-specific clinical data was provided for this case.
PP5 Not met PP5 requires a reputable source to have recently classified this variant as pathogenic. ClinVar classifies NM_006445.3:c.6247C>T as Benign (VariationID 321876; review status: criteria provided, single submitter; 3 clinical laboratories concur). No reputable source reports it as pathogenic.
clinvar
BA1 Met The allele frequency in the African/African American population exceeds 1%: gnomAD v2.1 AF=4.80% (1199/24,960 alleles, 31 homozygotes, grpmax FAF=4.58%); gnomAD v4.1 AF=4.90% (3673/75,010 alleles, 86 homozygotes, grpmax FAF=4.76%). The overall population AF is 0.47% (v2.1) and 0.27% (v4.1). The African subpopulation frequency far exceeds the BA1 threshold of >1% and is incompatible with a highly penetrant Mendelian disorder.
gnomad_v2 gnomad_v4
BS1 Met The allele frequency in the African/African American population exceeds 0.3%: gnomAD v2.1 AF=4.80%; gnomAD v4.1 AF=4.90%. The overall global AF is also elevated at 0.47% (v2.1). This is substantially above the BS1 threshold of >0.3% for a dominant disorder with high penetrance.
gnomad_v2 gnomad_v4
BS2 Met This variant has been observed in the homozygous state in 32 healthy individuals in gnomAD v2.1 and 89 healthy individuals in gnomAD v4.1. Observation in the homozygous state in population databases demonstrates that this variant does not cause a highly penetrant dominant or recessive disease in these individuals.
gnomad_v2 gnomad_v4
BS3 Not met BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect. No experimental functional studies specifically testing NM_006445.3:c.6247C>T were identified in the literature. While the synonymous nature and absence of splice impact are consistent with a benign effect, BS3 requires explicit functional data demonstrating no deleterious impact.
BS4 Not met BS4 requires lack of segregation with disease in affected family members. No segregation data was identified for this variant.
BP1 N/A BP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. NM_006445.3:c.6247C>T is a synonymous variant, not a missense variant.
BP2 Not met BP2 requires the variant to be observed in trans with a known pathogenic variant in a gene associated with a fully penetrant dominant disorder, OR observed in cis with a pathogenic variant in any inheritance pattern. No such observation was identified for NM_006445.3:c.6247C>T.
BP4 Met Multiple lines of computational evidence support a benign effect. SpliceAI predicts no significant splice impact (max delta score 0.01). REVEL and BayesDel scores are not available as this is a synonymous variant without missense consequence. The synonymous nature itself, combined with no predicted splice alteration, supports a benign interpretation.
spliceai
BP5 Not assessed BP5 requires an alternate molecular basis for disease to have been identified in the patient. No patient-specific clinical or molecular data was provided to assess whether an alternative cause explains the phenotype.
BP6 Met ClinVar classifies NM_006445.3:c.6247C>T as Benign (VariationID 321876; review status: criteria provided, single submitter). Three independent clinical laboratories concur on a benign classification, providing supporting evidence for a benign interpretation.
clinvar
BP7 Met NM_006445.3:c.6247C>T is a synonymous variant (p.Leu2083=) with SpliceAI predicting no significant splice impact (max delta score 0.01). No new splice site creation or disruption of the consensus splice site is predicted. The variant does not affect the encoded amino acid sequence.
spliceai
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.