NM_006445.3:c.6247C>T

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

Likely Benign

BS1 strong benign BP6 supporting benign BP7 supporting benign

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

The variant is a synonymous change (p.Leu2083=) with no predicted splice impact (SpliceAI max delta 0.01), so no loss-of-function or missense mechanism is supported.

It is present in gnomAD at 0.469% (v2.1) and 0.267% (v4.1) allele frequency with 32 and 89 homozygotes respectively, exceeding the 0.3% BS1 threshold for a disorder-causing variant in a rare dominant retinopathy gene (BS1, strong benign).

ClinVar reports the variant as Benign from three clinical laboratories, a reputable-source benign assertion applied at supporting strength (BP6).

As a synonymous variant with no splice impact and no evidence of high conservation, BP7 is applied at supporting strength.

No pathogenic criterion is met: PVS1, PS1, PM1, PM5, PP2, BP1, BP3, PM3, and PM4 are structurally inapplicable to a synonymous substitution, and no de novo, segregation, functional, case-prevalence, or phenotype evidence exists.

Per the generic ACMG/AMP 2015 combination rules, one strong benign criterion plus supporting benign criteria (BS1 + BP6 + BP7) supports Likely Benign.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	Synonymous variant (p.Leu2083=); it is not a nonsense, frameshift, or canonical +/-1,2 splice variant, so the generic PVS1 null-variant framework does not apply.	pvs1_gene_context pvs1_variant_assessment
PS1	N/A	Synonymous variant with no amino acid change, so no same-residue pathogenic missense comparator can exist.
PS2	Not met	No de novo occurrence of this variant has been reported in any source reviewed.
PS3	Not met	No variant-specific or systematic functional characterization of this variant exists in the reviewed literature; functional criteria cannot be applied.
PS4	Not met	No case-control or prevalence data indicate an enrichment of this variant in affected individuals.
PS5	Not met	Reputable sources report the variant as Benign, not pathogenic; no pathogenic assertion exists to support PS5.	clinvar
PM1	N/A	Synonymous variant; PM1 requires a missense alteration within a critical functional domain or hotspot, and no amino acid substitution occurs.
PM2	Not met	Allele frequency far exceeds the PM2 threshold: 0.469% in gnomAD v2.1 and 0.267% in gnomAD v4.1, with 32 and 89 homozygotes respectively, so absence from population databases is not supported.	gnomad_v2 gnomad_v4
PM5	N/A	Synonymous variant with no missense change; no same-residue pathogenic missense comparator is possible, and the PM5 candidate harvest found no candidates.	pm5_candidates
PM6	Not met	No de novo report (confirmed or assumed) for this variant was identified in any reviewed source.
PP1	Not met	No co-segregation data in affected family members is available for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation; this variant is synonymous.
PP3	Not met	Computational evidence does not support a deleterious effect: SpliceAI predicts no splice impact (max delta 0.01) and no missense predictors apply to a synonymous variant.	spliceai
PP4	Not met	No phenotype or family history data specific to this variant was provided; the criterion cannot be applied.
PP5	Not met	Reputable sources report the variant as Benign rather than pathogenic, and no expert-panel pathogenic assertion exists; PP5 is not supported.	clinvar
BA1	Not met	Overall allele frequency (0.469% in gnomAD v2.1) is below the 1% stand-alone benign threshold; the AFR subpopulation frequency (~4.8%) is high but does not meet BA1 at the population level.	gnomad_v2 gnomad_v4
BS1	Met	Allele frequency exceeds the 0.3% BS1 threshold for a disorder-causing variant: 0.469% in gnomAD v2.1 (1327/282876 alleles, 32 homozygotes) and 0.267% in gnomAD v4.1 (89 homozygotes), with ~4.8% frequency in the African/African American subpopulation, indicating the variant is too common to cause a rare dominant retinopathy.	gnomad_v2 gnomad_v4
BS2	Not met	Population database observations (including homozygotes) are not verified healthy-adult observations with full penetrance expected at an early age for PRPF8-associated dominant disease; BS2 is not strictly met, though BS1 already captures the frequency evidence.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrating absence of damaging effect on protein function or splicing are available for this variant.
BS4	Not met	No segregation data showing lack of segregation in affected family members is available.
BP1	N/A	BP1 applies to missense variants in genes for which only truncating variants cause disease; this is a synonymous variant.
BP2	Not met	No observation of the variant in trans with a pathogenic variant (or in cis with a pathogenic variant) is documented.
BP3	N/A	Skipped per task instructions: BP3 concerns in-frame insertions/deletions and is trivially not applicable to a single-nucleotide substitution.
BP4	Not met	Only a single computational line (SpliceAI max delta 0.01) is available; multiple independent lines of computational evidence of no impact are not met, and missense predictors do not apply to a synonymous variant (BP7 covers this variant type).	spliceai
BP5	Not met	No documented alternate molecular basis of disease in a case carrying this variant is available.
BP6	Met	ClinVar, a reputable source, reports this variant as Benign from three clinical laboratories (ClinVarID 321876); the underlying laboratory evidence is not available for independent evaluation, consistent with BP6.	clinvar
BP7	Met	The variant is synonymous (p.Leu2083=) and SpliceAI predicts no impact on splicing (max delta 0.01); no evidence indicates the nucleotide is highly conserved or that the change disrupts function.	spliceai
PM3	N/A	Skipped per task instructions: PM3 concerns recessive disease with a pathogenic variant in trans and is trivially not applicable to this autosomal dominant context.
PM4	N/A	Skipped per task instructions: PM4 concerns protein length changes and is trivially not applicable to a synonymous substitution.

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.