NM_006445.3:c.1855-13C>T

PRPF8 · NP_006436.3:p.? · NM_006445.3

GRCh37: chr17:1581001 G>A · GRCh38: chr17:1677707 G>A

Gene: PRPF8 Transcript: NM_006445.3

Final call

Benign

BA1 stand-alone benign BS1 strong benign BP4 supporting benign

Variant details

Gene

PRPF8

Transcript

NM_006445.3

Protein

NP_006436.3:p.?

gnomAD AF

0.002409459358964825 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The variant is present at high population frequency in gnomAD (v2.1 overall AF 0.43%, 30 homozygotes; v4.1 AF 0.24%, 77 homozygotes), and the African/African American subpopulation AF (4.5%) and grpmax FAF (4.3-4.5%) exceed the 1% stand-alone benign threshold, far exceeding expectations for an autosomal dominant RP13 allele; BA1 is met at stand-alone benign strength.

SpliceAI predicts no significant splice impact (max delta 0.12) and ClinVar reports the variant as Benign from 3 clinical laboratories with no conflicting pathogenic assertions.

No reviewed publication reports NM_006445.3:c.1855-13C>T, so no pathogenic literature evidence applies; all ClinVar-attached PMIDs (25741868, 26666451, 20301590, 22234150, 28492532) are framework or gene-level references without variant-specific data.

Under the generic ACMG/AMP combination rules, BA1 alone is sufficient for a Benign classification, and BA1 plus BS1 (strong benign) with BP4 (supporting benign) are concordant with Benign.

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	Intronic variant (NM_006445.3:c.1855-13C>T, intron 13) outside the canonical splice consensus (±1,2); the PVS1 variant assessment assigns bucket 'other' with apply_generic_pvs1_framework=false, so null-variant PVS1 does not apply.	pvs1_variant_assessment pvs1_gene_context
PS1	Not met	No pathogenic variant at the same nucleotide position (c.1855-13) has been reported; the variant is intronic with no protein consequence (p.?) so a same-amino-acid comparison is not possible.
PS2	Not met	No de novo occurrence of this variant has been reported in the reviewed literature or databases.
PS3	Not met	No functional studies have directly tested this variant or a systematically characterized range that includes intron 13 position -13; SpliceAI predicts no splice impact (max delta 0.12).	spliceai
PS4	Not met	No case-control or patient cohort data implicate this variant; ClinVar reports Benign from 3 clinical laboratories and population frequency is high.	clinvar gnomad_v2
PS5	Not met	ClinVar submissions are Benign (3 clinical laboratories); no reputable source reports this variant as pathogenic, so PS5 does not apply.	clinvar
PM1	N/A	Intronic variant with no protein consequence; PM1 domain-level criteria for missense/in-frame changes in a critical functional domain do not apply.
PM2	Not met	Population frequency (gnomAD v2.1 AF 0.43%; v4.1 AF 0.24%) far exceeds the 0.1% PM2 threshold; the variant is common in reference populations, so absence-from-controls does not apply.	gnomad_v2 gnomad_v4
PM3	N/A	Skipped as trivially not applicable: PM3 requires recessive disease with the variant observed in trans with a pathogenic variant; PRPF8-associated RP13 is autosomal dominant.
PM4	N/A	Skipped as trivially not applicable: protein length change (in-frame indel/stop-loss) does not apply to an intronic substitution with no protein consequence.
PM5	N/A	Skipped as trivially not applicable: intronic variant with no protein consequence; pm5_candidates.json found no same-residue missense comparator (PM5 mode 'unknown', residue context not parseable).	pm5_candidates
PM6	Not met	No de novo report for this variant was identified in the reviewed literature or databases.
PP1	Not met	No segregation data for this variant in affected family members have been reported.
PP2	Not met	Variant is intronic, not missense; additionally PRPF8-associated disease includes pathogenic missense variants, so a low rate of benign missense variation in the gene does not support pathogenicity here.
PP3	Not met	SpliceAI max delta 0.12 is below the 0.2 splice-altering threshold and predicts no significant splice impact; REVEL and BayesDel are not available for this intronic variant, so no in-silico evidence supports a damaging effect.	spliceai
PP4	Not met	No phenotype-specific data link this variant to retinitis pigmentosa or other PRPF8-associated phenotypes.
PP5	Not met	ClinVar reports the variant as Benign (not pathogenic) from 3 clinical laboratories; PP5 applies to reputable pathogenic assertions and, per the global PP5/BP6 rule, at supporting strength only for 3-star expert panel submissions, which is not the case here.	clinvar
BA1	Met	Highest observed population frequency exceeds the 1% BA1 threshold: African/African American AF 4.53% (gnomAD v2.1, 29 homozygotes) and 4.59% (v4.1, 75 homozygotes), with grpmax FAF 4.28% and 4.47% respectively; this is far too frequent for a rare autosomal dominant RP13 allele and is stand-alone benign.	gnomad_v2 gnomad_v4
BS1	Met	Overall allele frequency in gnomAD v2.1 (0.43%, 1217/281232 alleles) exceeds the 0.3% BS1 threshold, and the AFR subpopulation frequency (4.5%) far exceeds it; the variant is too frequent in reference populations to be a rare disease-causing allele.	gnomad_v2 gnomad_v4
BS2	Not met	Although homozygotes are observed in gnomAD (30 in v2.1, 77 in v4.1), the population cohort is not phenotype-confirmed healthy adults for an early-onset fully penetrant disorder; this frequency evidence is already captured under BA1/BS1.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrating absence of a damaging effect on gene or gene product are available for this variant.
BS4	Not met	No segregation data are available showing absence of segregation with disease in affected family members.
BP1	N/A	Variant is intronic, not a missense variant; additionally PRPF8-associated disease includes pathogenic missense variants, so BP1 (missense in a gene where only truncating variants cause disease) does not apply.
BP2	Not met	No data are available on observation of this variant in trans with a pathogenic variant or in cis with a benign variant.
BP3	N/A	Skipped as trivially not applicable: in-frame indel in a repetitive region does not apply to a single-nucleotide intronic substitution.
BP4	Met	SpliceAI predicts no significant splice impact (max delta 0.12, below the 0.2 splice-altering threshold) for this intronic variant 13 bp upstream of exon 14, consistent with a benign effect on splicing.	spliceai
BP5	Not met	No alternate molecular basis of disease (e.g., a distinct pathogenic mechanism in this gene) has been established for this case.
BP6	Not met	ClinVar reports Benign from 3 clinical laboratories, but per the global PP5/BP6 rule BP6 is applied at supporting strength only for 3-star expert panel submissions; this record is a non-expert-panel assertion ('criteria provided, multiple submitters, no conflicts'), so BP6 is not independently applied.	clinvar
BP7	N/A	Variant is not a synonymous or deep intronic variant (position -13 lies near the acceptor region); splice-impact prediction is assessed under BP4.	spliceai

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