NM_006445.3:c.4639-17T>G

PRPF8 · NP_006436.3:p.? · NM_006445.3

GRCh37: chr17:1563889 A>C · GRCh38: chr17:1660595 A>C

Gene: PRPF8 Transcript: NM_006445.3

Final call

Benign

BA1 stand-alone

Variant details

Gene

PRPF8

Transcript

NM_006445.3

Protein

NP_006436.3:p.?

gnomAD AF

0.01171060440670112 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

BA1 (Stand-alone Benign): gnomAD v4.1 African/African American allele frequency 14.95% (11,219/75,020 alleles, 875 homozygotes) far exceeds the >5% stand-alone benign threshold.

Overall classification: Benign, produced by the BA1 stand-alone rule under generic ACMG/AMP combination criteria.

Final determination: Generic ACMG/AMP 2015 rule: 1 BA1 (stand-alone benign, population allele frequency >5%) is sufficient alone to classify a variant as Benign.

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: deep intronic change 17 bp upstream of the exon, not a nonsense, frameshift, or canonical splice-site null variant.	pvs1_variant_assessment pvs1_gene_context spliceai pvs1_generic_framework
PS1	N/A	Not applicable: no amino acid change (p.?) results, so there is no protein change to compare with a known pathogenic variant.
PS2	Not assessed	Not assessed: no parental or proband data were available to confirm a de novo occurrence.
PS3	Not assessed	Not assessed: no functional assay data (e.g., splicing assay) for this variant were available.
PS4	Not assessed	Not assessed: no case-control or case-series evidence of enrichment in PRPF8-related disease was available.
PM1	N/A	Not applicable: intronic variant with no codon or residue change, so no mutational hotspot location to evaluate.
PM2	Not met	Not met: variant is common (gnomAD v4.1 African/African American AF 14.95%), the opposite of the rarity PM2 requires.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no affected individual with this variant in trans with a pathogenic PRPF8 variant.	PMID:25741868
PM4	N/A	Not applicable: single-nucleotide intronic substitution, not an in-frame indel or stop-loss change.	pvs1_variant_assessment spliceai
PM5	N/A	Not applicable: no amino acid substitution occurs, so no same-residue missense comparison can be made.
PM6	Not assessed	Not assessed: no reported de novo occurrence, with or without confirmed parental identity.
PP1	Not assessed	Not assessed: no pedigree, segregation, or informative meiosis data were available.
PP2	N/A	Not applicable: variant is intronic, not missense, so the missense-based PP2 rule cannot apply.
PP3	Not met	Not met: SpliceAI max delta 0.135 falls in the inconclusive 0.1-0.2 band, below the >=0.2 splice-altering threshold.	spliceai
PP4	Not assessed	Not assessed: no phenotype data link this variant to a PRPF8-related disorder.	clinvar
PP5	Not met	Not met: no pathogenic or likely pathogenic expert-panel ClinVar assertion exists for this exact variant.	clinvar
BA1	Met	Met (stand-alone benign): gnomAD v4.1 African/African American allele frequency 14.95% (875 homozygotes) far exceeds the >5% threshold.	gnomad_v4 gnomad_v2 gnomad_canada PMID:25741868
BS1	N/A	Not applicable: BA1 is already met at stand-alone benign strength from the same population-frequency evidence.	gnomad_v4
BS2	Not assessed	Not assessed: population records lack the phenotype and age data needed to confirm observation in healthy adults.	gnomad_v4 gnomad_v2 gnomad_canada PMID:25741868
BS3	Not assessed	Not assessed: no functional assay demonstrating normal splicing or protein function was available.
BS4	Not assessed	Not assessed: no family data showing the variant does not segregate with disease.
BP1	N/A	Not applicable: requires a missense variant; this intronic change produces no amino acid alteration.
BP2	Not assessed	Not assessed: no data establish this variant in cis or in trans with a pathogenic PRPF8 variant.	PMID:25741868
BP3	N/A	Not applicable: not an in-frame indel in a repeat region, and no predicted protein length change.	pvs1_variant_assessment
BP4	Not met	Not met: SpliceAI max delta 0.135 exceeds the <0.1 threshold needed to predict no splice effect.	spliceai
BP5	Not assessed	Not assessed: no individual with this variant and a phenotype explained by an alternative diagnosis.
BP6	Not met	Not met: no benign or likely benign expert-panel ClinVar assertion exists for this exact variant.	clinvar
BP7	N/A	Not applicable: variant is intronic, not synonymous coding, so the synonymous no-splice-impact rule does not apply.

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.