Variant classification summary

NM_006445.3:c.1666C>T

PRPF8 · NP_006436.3:p.(Leu556=) · NM_006445.3

GRCh37: chr17:1582109 G>A · GRCh38: chr17:1678815 G>A

Gene: PRPF8 Transcript: NM_006445.3

Final call

Likely Benign

BS1 strong benign BP4 supporting benign BP7 supporting benign

Variant details

Gene

PRPF8

Transcript

NM_006445.3

Protein

NP_006436.3:p.(Leu556=)

gnomAD AF

0.0003543731003557361 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_006445.3:c.1666C>T (p.Leu556=) is a synonymous variant in PRPF8, a gene associated with autosomal dominant retinitis pigmentosa.

2

This variant is present in population databases at frequencies too high for a highly penetrant pathogenic variant: gnomAD v4.1 grpmax filtering allele frequency is 0.632%, with 3 homozygotes observed in the African/African American population (AF = 0.681%).

3

SpliceAI predicts no impact on splicing (max delta score = 0.00), consistent with a synonymous variant that does not alter the gene product or create/disrupt splice sites.

4

ClinVar reports this variant as Benign (2 clinical laboratories) or Likely benign (1 clinical laboratory), though review status is single-submitter level (1-star).

5

This variant meets BS1 (strong benign, allele frequency >0.3%), BP4 (supporting benign, no predicted splice impact), and BP7 (supporting benign, synonymous variant with no splice effect). No pathogenic criteria are met.

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 (NP_006436.3:p.(Leu556=)) does not alter the protein sequence; PVS1 requires a predicted null variant mechanism (nonsense, frameshift, canonical splice, initiation codon, or exon deletion).	pvs1_variant_assessment
PS1	N/A	Synonymous variant produces no amino acid change; PS1 requires a variant with the same amino acid change as an established pathogenic missense variant.
PS2	N/A	No de novo data available for NM_006445.3:c.1666C>T.
PS3	Not met	No functional data identified for NM_006445.3:c.1666C>T. SpliceAI predicts no splice impact (max delta score = 0.00). No in vitro or in vivo functional studies of this variant were identified in the literature.	spliceai
PS4	Not met	No case-specific prevalence data available. The variant is observed in population databases at frequencies inconsistent with a highly penetrant pathogenic variant (3 homozygotes in gnomAD v4.1).	gnomad_v2 gnomad_v4 clinvar
PS5	N/A	Synonymous variant produces no amino acid change; PS5 requires a novel missense change at an amino acid residue where a different pathogenic missense change has been established.
PM1	Not met	This synonymous variant is not located in a statistically significant mutational hotspot (cancerhotspots.org negative). SpliceAI predicts no splice disruption (max delta = 0.00). No evidence that this synonymous change disrupts a critical functional domain.	spliceai
PM2	Not met	Present in gnomAD at frequencies exceeding the PM2 threshold of <0.1%. gnomAD v4.1 grpmax filtering allele frequency is 0.632% (511/75,040 alleles in African/African American population with 3 homozygotes).	gnomad_v2 gnomad_v4
PM5	N/A	Synonymous variant with no amino acid change; PM5 requires a different missense alteration at the same amino acid residue compared to an established pathogenic missense variant. PM5 candidate harvesting was unable to parse a missense residue context.	pm5_candidates
PM6	N/A	No de novo data available for this variant; no trio or parentage-confirmed de novo observations were identified in ClinVar or the literature.
PP1	Not met	No cosegregation data available for this variant.
PP2	N/A	Synonymous variant; PP2 is specific to missense variants in genes with a low rate of benign missense variation.
PP3	Not met	No computational evidence supports a deleterious effect. SpliceAI predicts no splice impact (max delta = 0.00). REVEL and BayesDel scores are not available for this variant.	spliceai
PP4	Not met	No patient phenotype data available to assess specificity to PRPF8-associated disease (retinitis pigmentosa).
PP5	Not met	ClinVar classification for this variant is Benign, not Pathogenic. PP5 requires a pathogenic assertion from a reputable source.	clinvar
BA1	Not met	Maximum population allele frequency (gnomAD v4.1 grpmax FAF = 0.632%) is below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Met	The allele frequency of this variant is greater than expected for a PRPF8-associated disorder (retinitis pigmentosa). gnomAD v4.1 grpmax filtering allele frequency is 0.632%, exceeding the BS1 threshold of >0.3%. In the African/African American population, the allele frequency is 0.681% (511/75,040 alleles) with 3 homozygotes, confirming this variant is too common to cause a highly penetrant dominant disease.	gnomad_v2 gnomad_v4
BS2	Not met	No confirmed clinical observation of this variant in a healthy adult individual for a fully penetrant dominant disorder expected at an early age. However, the presence of 3 homozygotes in gnomAD v4.1 strongly suggests this variant is tolerated in the homozygous state in population databases screened for severe pediatric disease.	gnomad_v4
BS3	Not met	No functional studies demonstrating a benign effect for NM_006445.3:c.1666C>T were identified. SpliceAI predicts no splice impact (max delta = 0.00), but in silico predictions alone are insufficient to meet BS3.	spliceai
BS4	Not met	No segregation data available. BS4 requires a lack of cosegregation in affected family members.
BP1	N/A	Synonymous variant; BP1 is specific to missense variants in genes where primarily truncating variants are known to cause disease.
BP2	Not met	No data on observation of this variant in trans with a known pathogenic PRPF8 variant.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splice alteration (max delta score = 0.00). As a synonymous variant without predicted splicing effects, the nucleotide substitution is not expected to alter protein sequence or function.	spliceai
BP5	Not met	No data indicating an alternate molecular basis for disease in an individual carrying this variant.
BP6	Not met	ClinVar classifies this variant as Benign, but the review status is only 'criteria provided, single submitter' (1-star). BP6 requires a reputable source with strong evidence, typically an expert panel (3-star) review. The available ClinVar assertion does not reach the threshold for BP6 application.	clinvar
BP7	Met	NM_006445.3:c.1666C>T is a synonymous variant (p.Leu556=) for which SpliceAI predicts no impact on splicing (max delta score = 0.00). The nucleotide is observed at appreciable frequency in population databases (gnomAD v4.1: 3 homozygotes, African/African American AF = 0.681%), consistent with a lack of strong evolutionary constraint at this position.	spliceai gnomad_v4

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