Variant classification summary

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

Benign

BA1 stand-alone benign BS1 supporting benign BS2 strong BP4 supporting 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

1

NM_006445.3:c.6247C>T (p.Leu2083=) is a synonymous variant in PRPF8 with a maximum credible population allele frequency of 4.58% in gnomAD v2.1 (grpmax FAF=0.0458), well above the BA1 stand-alone benign threshold of >1%, and observed in 32 homozygotes.

2

This variant has been observed in the homozygous state in 32 individuals in gnomAD v2.1 and 89 in v4.1, which is incompatible with autosomal dominant PRPF8-associated retinitis pigmentosa (BS2).

3

SpliceAI predicts no splicing impact (max delta score=0.01), consistent with a neutral synonymous change (BP7, BP4).

4

Three independent clinical laboratories have classified this variant as Benign in ClinVar (ClinVar ID 321876), providing additional supporting evidence (BP6).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong 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=) with no predicted splice impact (SpliceAI max delta=0.01); does not meet PVS1 null-variant criteria per ClinGen SVI framework (PMC6185798).	pvs1_variant_assessment pvs1_generic_framework spliceai
PS1	N/A	Synonymous variant with no amino acid alteration; PS1 requires a different nucleotide change resulting in the same amino acid change as a previously established pathogenic variant.
PS2	Not met	No de novo observation with confirmed maternity and paternity has been reported for this variant.
PS3	Not met	No functional studies testing this specific variant or a systematically characterized range including position 6247 were identified in the reviewed literature.
PS4	Not met	No case-control data demonstrating enrichment in affected individuals; the variant is common in population databases (gnomAD v2.1 AF=0.47%, 32 homozygotes), inconsistent with prevalence of PRPF8-associated retinitis pigmentosa.	gnomad_v2 gnomad_v4
PS5	Not met	ClinVar classification for this variant is Benign (3 clinical laboratories, ClinVar ID 321876); no reputable source has reported it as pathogenic.	clinvar
PM1	N/A	Synonymous variant with no predicted functional consequence; PM1 domain-level assessment is not applicable for a variant that does not alter the protein sequence.	spliceai
PM2	Not met	This variant is present in gnomAD at high frequency: v2.1 AF=0.47% (1327/282876 alleles, 32 homozygotes), v4.1 AF=0.27% (4309/1614142 alleles, 89 homozygotes). Well above the PM2 threshold of <0.1%.	gnomad_v2 gnomad_v4
PM5	N/A	Synonymous variant (p.Leu2083=); no amino acid alteration to compare with other missense changes at the same residue. PM5 candidate harvesting confirmed not applicable.	pm5_candidates
PM6	Not met	No de novo observation (with or without confirmed parentage) has been reported for this variant.
PP1	Not met	No co-segregation data are available for this variant.
PP2	N/A	Synonymous variant; PP2 applies only to missense variants in genes with a low rate of benign missense variation.
PP3	Not met	REVEL and BayesDel scores are unavailable for this variant; SpliceAI predicts no splicing impact (max delta=0.01). No in silico evidence supports a deleterious effect.	spliceai
PP4	Not met	No patient phenotype or family history data were provided for this case; PP4 cannot be assessed.
PP5	Not met	ClinVar reports this variant as Benign from 3 clinical laboratories (ClinVar ID 321876). No reputable source has reported it as pathogenic. ClinVar review status is 1-star ('criteria provided, single submitter'), not meeting the 3-star expert panel threshold for automatic PP5 application.	clinvar
BA1	Met	This variant has a maximum credible population allele frequency of 4.58% in gnomAD v2.1 (grpmax FAF=0.0458484) and 4.76% in gnomAD v4.1 (grpmax FAF=0.0476449), well above the 1% BA1 threshold. Observed in 32 homozygotes in v2.1 and 89 homozygotes in v4.1, which is incompatible with a rare autosomal dominant disorder.	gnomad_v2 gnomad_v4
BS1	Met	This variant has a global allele frequency of 0.47% in gnomAD v2.1 and 0.27% in v4.1, exceeding the BS1 threshold of >0.3%. The frequency is far greater than expected for PRPF8-associated autosomal dominant retinitis pigmentosa. (Note: BA1 at stand-alone benign level subsumes this evidence.)	gnomad_v2 gnomad_v4
BS2	Met	This variant has been observed in the homozygous state in 32 individuals in gnomAD v2.1 and 89 individuals in gnomAD v4.1. Given that PRPF8-associated disease (retinitis pigmentosa) is autosomal dominant with full penetrance, the presence of numerous healthy homozygotes in population databases constitutes strong evidence for a benign classification.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrating a lack of damaging effect were identified for this variant in the reviewed literature.
BS4	Not met	No segregation data are available to assess lack of co-segregation with disease.
BP1	N/A	Synonymous variant; BP1 applies only to missense variants in genes where truncating variants are the primary disease mechanism.
BP2	Not met	No data on observation in trans with a known pathogenic variant are available.
BP3	N/A	Skipped per case directive: variant is a substitution, not an in-frame deletion/insertion in a repetitive region.
BP4	Met	SpliceAI predicts no splicing impact for this synonymous variant (max delta score=0.01), supporting a lack of functional consequence. REVEL and BayesDel scores are not available for this variant.	spliceai
BP5	Not met	No evidence that this variant is found in a case with an alternate molecular basis for disease.
BP6	Met	This variant has been classified as Benign by 3 independent clinical laboratories in ClinVar (Illumina, ARUP Laboratories, Labcorp/Invitae; ClinVar ID 321876). Although the aggregate review status is 1-star ('criteria provided, single submitter'), the concordant benign classification from multiple clinical testing laboratories provides supporting evidence for a benign interpretation.	clinvar
BP7	Met	This is a synonymous variant (p.Leu2083=) with no predicted impact on splicing. SpliceAI analysis yields a max delta score of 0.01, indicating no creation or disruption of splice sites. These findings are consistent with a neutral effect, satisfying BP7.	spliceai

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