Variant classification summary

NM_006445.3:c.3081A>T

PRPF8 · NP_006436.3:p.(Ser1027=) · NM_006445.3

GRCh37: chr17:1577954 T>A · GRCh38: chr17:1674660 T>A

Gene: PRPF8 Transcript: NM_006445.3

Final call

VUS

PM2 supporting BP7 supporting

Variant details

Gene

PRPF8

Transcript

NM_006445.3

Protein

NP_006436.3:p.(Ser1027=)

gnomAD AF

7.747815425962495e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): gnomAD v4.1 overall allele frequency 0.00775% (below 0.1%) with no homozygotes.

2

BP7 (Supporting): SpliceAI max delta score 0.005 (below 0.1), indicating no significant splice impact.

3

VUS: one supporting pathogenic and one supporting benign criterion conflict; no ACMG/AMP 2015 combination rule is satisfied.

Final determination: Generic ACMG/AMP 2015 fallback: with only one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP7) met, none of the defined Pathogenic/Likely Pathogenic/Benign/Likely Benign combinations are satisfied, so the variant defaults to Uncertain Significance.

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	Not applicable: this synonymous change (p.(Ser1027=)) triggers no null-variant mechanism such as nonsense-mediated decay.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: a synonymous change produces no altered amino acid to compare against previously established pathogenic variants.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no parental testing or de novo confirmation for this variant was available.
PS3	Not assessed	Not assessed: no wet-lab functional assay for this specific variant was available; only in silico SpliceAI data.
PS4	Not assessed	Not assessed: no case-control enrichment or affected-case series for this exact variant was identified.
PM1	N/A	Not applicable: PM1 applies only to missense variants; this is a synonymous substitution.	generic_acmg_combination_rules
PM2	Met	Met (supporting): gnomAD v4.1 overall allele frequency 0.00775%, below the 0.1% threshold, with no homozygotes.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no data on a second allele, phase, or inheritance for this variant was available.
PM4	N/A	Not applicable: a synonymous change causes no in-frame insertion/deletion or protein length change.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense change; this synonymous variant produces none.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no clinical record documents a presumed de novo occurrence of this variant.
PP1	Not assessed	Not assessed: no family pedigree or cosegregation data was available for this variant.
PP2	N/A	Not applicable: PP2 applies only to missense variants; this is a synonymous substitution.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta score 0.005, well below the >0.2 PP3 threshold.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no phenotype description for an individual carrying this exact variant was available.
PP5	Not met	Not met: ClinVar entry 891301 shows conflicting single-submitter classifications with no expert-panel submission.	clinvar
BA1	Not met	Not met: highest population frequency 0.01026%, far below the >1% BA1 threshold.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: highest population frequency 0.01026%, below the >0.3% BS1 threshold.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: no documented observation of the variant in healthy adults with an age-appropriate phenotype.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no wet-lab functional study showing absence of a damaging effect was available.
BS4	Not assessed	Not assessed: no affected or unaffected relatives tested for the variant were available for segregation.
BP1	N/A	Not applicable: BP1 applies only to missense variants; this is a synonymous substitution.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no evidence of the variant in trans or cis with a pathogenic variant was available.
BP3	N/A	Not applicable: a synonymous change does not alter protein length within a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: splice-impact evidence for this synonymous variant is captured by BP7; applying BP4 would double-count it.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no alternate molecular diagnosis explaining the patient's phenotype was documented.
BP6	Not met	Not met: the ClinVar likely-benign submission is from a single laboratory, not an expert panel.	clinvar
BP7	Met	Met (supporting): SpliceAI max delta score 0.005, below the 0.1 threshold, indicating no significant splice impact.	spliceai generic_acmg_combination_rules

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.