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.1 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.2 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.3
PRPF8
Final classification
Benign
PRPF8 c.1855-13C>T · p.?
PRPF8
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.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong benign, BP4 supporting benign; combination = 1 stand-alone benign + 1 strong benign + 1 supporting benign, which maps to Benign.
Classification rationale
BA1BS1BP4
Benign
PRPF8 c.1855-13C>T
BA1 + BS1 + BP4
→
Benign
Gene diagram
· NM_006445.3 · variants mapped to exon structure
PRPF8
NM_006445.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 17 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BA1
stand-alone
Benign
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 v2.1 AFR AF 4.5333% (1120/24706 alleles29 homozygotes)grpmax FAF 4.2791%
✓
BS1
strong
Benign
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 v2.1 total AF 0.4327% (30 homozygotes)gnomAD v4.1 total AF 0.2409% (77 homozygotes) with AFR AF 4.59%
✓
BP4
supporting
review
Benign
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 max delta 0.12 (acceptor/donor gain/loss all below significance)
Assessed · not applied
Pathogenic
PS1
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
No de novo occurrence of this variant has been reported in the reviewed literature or databases.
PS3
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).
PS4
No case-control or patient cohort data implicate this variant; ClinVar reports Benign from 3 clinical laboratories and population frequency is high.
PM2
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.
PM6
No de novo report for this variant was identified in the reviewed literature or databases.
PP1
No segregation data for this variant in affected family members have been reported.
PP2
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
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.
PP4
No phenotype-specific data link this variant to retinitis pigmentosa or other PRPF8-associated phenotypes.
PP5
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.
Benign
BS2
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.
BS3
No functional studies demonstrating absence of a damaging effect on gene or gene product are available for this variant.
BS4
No segregation data are available showing absence of segregation with disease in affected family members.
BP2
No data are available on observation of this variant in trans with a pathogenic variant or in cis with a benign variant.
BP5
No alternate molecular basis of disease (e.g., a distinct pathogenic mechanism in this gene) has been established for this case.
BP6
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.
N/A · 8
PVS1 · PM1 · PM3 · PM4 · PM5 · BP1 · BP3 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.00240946; MAF= 0.24095%, 3888/1613640 alleles, homozygotes = 77) and has highest observed frequency in the African/African American population (AF= 0.0459363; MAF= 4.59363%, 3441/74908 alleles, homozygotes = 75); grpmax FAF= 0.0446555.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00432739; MAF= 0.43274%, 1217/281232 alleles, homozygotes = 30) and has highest observed frequency in the African/African American population (AF= 0.0453331; MAF= 4.53331%, 1120/24706 alleles, homozygotes = 29); grpmax FAF= 0.0427907.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0029376564030029377, 54/18382 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.24%
· 3888 / 1,613,640
77 hom · FAF 4.5%
77 hom · FAF 4.5%
African/African American 3441 / 74,908 |
4.6% 75 hom |
Middle Eastern 18 / 6,056 |
0.3% |
Remaining individuals 177 / 62,496 |
0.28% 1 hom |
Admixed American 159 / 59,968 |
0.27% |
South Asian 20 / 91,070 |
0.022% 1 hom |
European (non-Finnish) 73 / 1,180,008 |
0.0062% |
+ 4 not observed (European (Finnish), Amish, East Asian, Ashkenazi Jewish)
gnomAD v2.1
0.43%
· 1217 / 281,232
30 hom · FAF 4.3%
30 hom · FAF 4.3%
African/African American 1120 / 24,706 |
4.5% 29 hom |
Admixed American 71 / 35,358 |
0.2% |
Remaining individuals 10 / 7,176 |
0.14% |
South Asian 8 / 30,554 |
0.026% 1 hom |
European (non-Finnish) 8 / 128,118 |
0.0062% |
+ 3 not observed (Ashkenazi Jewish, East Asian, European (Finnish))
gnomAD Canada 🇨🇦
0.29%
· 54 / 18,382
0 hom · FAF 3.1%
0 hom · FAF 3.1%
African/African American 41 / 1,018 |
4% |
Middle Eastern 1 / 144 |
0.69% |
Latino/Admixed American 4 / 832 |
0.48% |
Remaining individuals 3 / 1,136 |
0.26% |
European (non-Finnish) 5 / 11,714 |
0.043% |
+ 4 not observed (Ashkenazi Jewish, East Asian, European (Finnish), South Asian)
ClinVar
This variant has been reported in ClinVar as Benign (3 clinical laboratories). (ClinVarID = 321908)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links
Triaged references · 5 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
26666451 ↗
In Vivo CRISPR/Cas9 Gene Editing Corrects Retinal Dystrophy in the S334ter-3 Rat Model of Autosomal Dominant Retinitis Pigmentosa.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR