Variant classification summary

NM_006445.3:c.2013A>G

PRPF8 · NP_006436.3:p.(Thr671=) · NM_006445.3

GRCh37: chr17:1580438 T>C · GRCh38: chr17:1677144 T>C

Gene: PRPF8 Transcript: NM_006445.3

Final call

VUS

BP4 supporting

Variant details

Gene

PRPF8

Transcript

NM_006445.3

Protein

NP_006436.3:p.(Thr671=)

gnomAD AF

0.00017783032137099123 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 (Supporting): synonymous variant (p.Thr671=) with SpliceAI max delta 0.004, far below the 0.1 threshold, indicating no predicted splice impact.

2

Overall: Variant of Uncertain Significance - a single supporting benign criterion matches no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination rule.

Final determination: Under the generic ACMG/AMP 2015 combination rules (Richards et al., PMID:25741868), the single supporting benign criterion BP4 meets no Benign (BA1 alone; 2 BS) or Likely Benign (1 BS + 1 BP; 2 BP) threshold and no pathogenic combination is met, so the variant is classified as Variant of 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: synonymous substitution (p.Thr671=) produces no null variant, so no nonsense-mediated decay or truncation mechanism applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: synonymous change produces no altered amino acid to compare against a previously pathogenic variant at this position.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no de novo observation with parental testing exists for this variant in any clinical source.	clinvar PMID:28492532 generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no functional assay data exist; SpliceAI (max delta 0.004) is in-silico and cannot substitute.	spliceai PMID:28492532
PS4	Not assessed	Not assessed: no case-control or affected-cohort frequency exists; gnomAD documents only general-population frequency.	gnomad_v2 gnomad_v4
PM1	N/A	Not applicable: synonymous variant produces no altered residue to evaluate for mutational hotspot or critical-domain membership.	generic_acmg_combination_rules
PM2	Not met	Not met: highest subpopulation frequency (South Asian 0.284-0.320%) far exceeds the 0.1% threshold, so the variant is not rare.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	N/A	Not applicable: PRPF8 disease (RP13) is autosomal dominant, and no trans-phase pathogenic variant is documented.	generic_acmg_combination_rules clinvar
PM4	N/A	Not applicable: synonymous substitution causes no protein length change, leaving nothing for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at Thr671 to compare against a different pathogenic missense at the same residue.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no assumed de novo event or parental testing data exist for this variant.	clinvar PMID:28492532 generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no segregation analysis or affected-family genotype data exist for this variant.	clinvar PMID:28492532 generic_acmg_combination_rules
PP2	N/A	Not applicable: synonymous variant involves no missense change, so the gene's missense-constraint properties do not apply.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.004 is far below the >0.2 PP3 threshold; no other computational evidence supports pathogenicity.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no clinical case or phenotype data exist to evaluate phenotype specificity for this variant.	clinvar
PP5	Not met	Not met: no expert-panel ClinVar pathogenic classification exists; the sole submission is a single-laboratory Benign label.	clinvar
BA1	Not met	Not met: maximum allele frequency (South Asian 0.32%) is far below the >1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Not met	Not met: population-maximum allele frequencies (grpmax FAF 0.256-0.269%) stay below the 0.3% threshold. Flagged for human review: borderline South Asian frequency (0.28-0.32%).	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS2	Not met	Not met: gnomAD homozygotes (4 in v4.1) do not satisfy the healthy-adult phenotype requirement. Flagged for human review: homozygous observations as potential BS2-relevant signal.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no well-established functional studies exist; SpliceAI max delta 0.004 is in-silico, not a validated assay.	spliceai PMID:28492532
BS4	Not assessed	Not assessed: no affected-family non-segregation data exist for this variant.	clinvar PMID:28492532 generic_acmg_combination_rules
BP1	N/A	Not applicable: synonymous variant involves no missense change, so the truncating-mechanism criterion does not apply.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no phase information (trans or cis with a pathogenic variant) is documented for this variant.	generic_acmg_combination_rules clinvar
BP3	N/A	Not applicable: synonymous substitution causes no in-frame length change in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (Supporting): SpliceAI max delta 0.004 is far below the <0.1 BP4 threshold, indicating no predicted splice impact.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no case-level data exist to evaluate an alternate molecular basis for disease.
BP6	Not met	Not met: the Benign ClinVar label comes from a single laboratory, not an expert panel, so it cannot trigger BP6.	clinvar
BP7	Not met	Not met: crediting BP7 would double-count the SpliceAI prediction already used for BP4, and conservation data are absent.	spliceai generic_acmg_combination_rules gnomad_v2 gnomad_v4

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.