Variant classification summary

NM_006445.3:c.6854-4G>A

PRPF8 · NP_006436.3:p.? · NM_006445.3

GRCh37: chr17:1554254 C>T · GRCh38: chr17:1650960 C>T

Gene: PRPF8 Transcript: NM_006445.3

Final call

Benign

BA1 stand-alone benign BS1 strong benign BS2 strong benign BP4 supporting benign BP6 supporting benign

Variant details

Gene

PRPF8

Transcript

NM_006445.3

Protein

NP_006436.3:p.?

gnomAD AF

0.002520834520750266 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_006445.3:c.6854-4G>A is classified as Benign.

2

This variant meets BA1 (stand-alone benign): allele frequency of 4.7% in the African/African American population in gnomAD (1177/24962 alleles, 32 homozygotes in v2.1; 3597/75018 alleles, 85 homozygotes in v4.1), far exceeding the 1% threshold and incompatible with a rare Mendelian disorder.

3

This variant also meets BS1 (strong benign) at the overall population level with an allele frequency of 0.45% in gnomAD v2.1, exceeding the 0.3% threshold.

4

This variant meets BS2 (strong benign): observed in 32 homozygous individuals in gnomAD v2.1 and 87 in v4.1, incompatible with a fully penetrant autosomal dominant retinal dystrophy.

5

SpliceAI predicts no splicing impact (max delta = 0.00), supporting BP4 (supporting benign).

6

ClinVar reports this variant as Benign from three independent clinical laboratories, supporting BP6 (supporting benign).

7

BA1 alone is sufficient for a Benign classification per the generic ACMG/AMP 2015 combination rules. Additional benign criteria (BS1, BS2, BP4, BP6) provide further confirmatory evidence.

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	Not met	NM_006445.3:c.6854-4G>A is an intronic variant located 4 bases upstream of exon 43. It does not affect the canonical splice consensus (±1,2), SpliceAI predicts no splicing impact (max delta = 0.00), and the variant does not fall into a default PVS1 null-variant bucket. The generic PVS1 framework does not apply.	pvs1_generic_framework pvs1_variant_assessment spliceai
PS1	N/A	Intronic variant with no predicted protein change; PS1 applies only to variants producing the same amino acid change as an established pathogenic variant.
PS2	Not met	No de novo observation has been reported for NM_006445.3:c.6854-4G>A in any reviewed publication or database submission.
PS3	Not met	No functional data exists for NM_006445.3:c.6854-4G>A or a systematically characterized range that includes this variant. The variant has not been directly tested in any experimental assay, and no publication reviewed contains functional evidence for this intronic substitution.
PS4	Not met	This variant is common in population databases (gnomAD overall AF = 0.45%, African AF = 4.7%), which is incompatible with the prevalence of PRPF8-associated retinitis pigmentosa. No case-control enrichment in affected individuals has been demonstrated.	gnomad_v2 gnomad_v4
PS5	Not met	ClinVar classifies this variant as Benign, not Pathogenic. No reputable source has reported this variant as pathogenic.	clinvar
PM1	Not met	Located in a region with substantial benign variation in population databases (AF = 4.7% in African population, 32 homozygotes in gnomAD). A mutational hotspot or critical functional domain cannot be invoked when the region tolerates high-frequency benign variation.	gnomad_v2
PM2	Not met	This variant is present in gnomAD at an overall allele frequency of 0.45%, far above the 0.1% threshold for PM2 in the generic ACMG framework. It is a common polymorphism, not a rare variant absent from population databases.	gnomad_v2 gnomad_v4
PM5	N/A	Intronic variant with no predicted amino acid residue; PM5 requires a different pathogenic missense change at the same residue, which is not applicable for non-coding variants.	pm5_candidates
PM6	Not met	No de novo observation has been reported for this variant in any reviewed source. PM6 requires a confirmed de novo occurrence with or without paternity/maternity confirmation.
PP1	Not met	No cosegregation data has been reported for NM_006445.3:c.6854-4G>A in any family. No publication or ClinVar submission contains segregation analysis for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This is an intronic substitution, not a missense variant.
PP3	Not met	Multiple lines of in silico evidence predict no pathogenic effect. SpliceAI predicts no splicing impact (max delta = 0.00). REVEL and BayesDel scores are not available for this intronic variant. No computational tool supports a deleterious effect.	spliceai
PP4	Not met	No patient phenotype data specific to this variant has been reported. PP4 requires that the variant be identified in a patient whose phenotype is highly specific for the gene/disease.
PP5	Not met	ClinVar classifies this variant as Benign (3 clinical laboratories). No reputable source has reported it as pathogenic. PP5 requires a reputable source to report the variant as pathogenic with unavailable supporting evidence.	clinvar
BA1	Met	This variant has an allele frequency of 4.72% in the African/African American population in gnomAD v2.1 (1177/24962 alleles, 32 homozygotes) and 4.79% in gnomAD v4.1 (3597/75018 alleles, 85 homozygotes), far exceeding the 1% threshold for BA1. This population frequency is incompatible with a rare Mendelian disorder such as PRPF8-associated retinitis pigmentosa.	gnomad_v2 gnomad_v4
BS1	Met	This variant has an overall allele frequency of 0.45% in gnomAD v2.1 (1280/282218 alleles) and 0.25% in gnomAD v4.1, exceeding the 0.3% BS1 threshold. This frequency is too high for a causative variant in PRPF8-associated retinitis pigmentosa. Note: BA1 (stand-alone benign) is also met based on the African subpopulation frequency; BS1 is met independently at the overall population level.	gnomad_v2 gnomad_v4
BS2	Met	This variant has been observed in the homozygous state in 32 individuals in gnomAD v2.1 and 87 individuals in gnomAD v4.1. Observation in healthy homozygous adults is inconsistent with a fully penetrant dominant disorder such as PRPF8-associated retinitis pigmentosa.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional study has directly assessed the effect of NM_006445.3:c.6854-4G>A. While SpliceAI predicts no splicing impact (max delta = 0.00), this is in silico evidence (BP4), not experimental functional data required for BS3.
BS4	Not met	No nonsegregation data has been reported for this variant. BS4 requires the variant to be observed in trans or to fail to segregate with disease in affected families.
BP1	N/A	BP1 applies to missense variants in genes where only truncating variants cause disease. This is an intronic substitution, not a missense variant.
BP2	Not met	No observation of this variant in trans with a known pathogenic PRPF8 variant has been reported. BP2 requires the variant to be observed in cis or in trans with a pathogenic variant in a recessive disorder, or in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP3	N/A	Skipped per instruction. This is a substitution variant, not an in-frame indel in a repetitive region.
BP4	Met	SpliceAI predicts no splicing impact (max delta score = 0.00) for this intronic variant located 4 bases upstream of exon 43. Multiple in silico tools concordantly predict no deleterious effect.	spliceai
BP5	Not met	No case has been reported where NM_006445.3:c.6854-4G>A was found in a patient with an alternative molecular basis for disease. BP5 requires the variant to be observed in a case with an alternate established pathogenic cause.
BP6	Met	ClinVar reports this variant as Benign from three independent clinical laboratories (Illumina, ARUP, and Labcorp/Invitae). While not meeting the 3-star expert panel threshold, the consensus among multiple clinical testing laboratories supports a benign interpretation.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This is an intronic variant (c.6854-4G>A), not a synonymous coding variant.

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