NM_006445.3:c.6854-4G>A is classified as Benign. 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.1 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.2 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.3 SpliceAI predicts no splicing impact (max delta = 0.00), supporting BP4 (supporting benign).4 ClinVar reports this variant as Benign from three independent clinical laboratories, supporting BP6 (supporting benign).5 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.6
PRPF8
Final classification
Benign
PRPF8 c.6854-4G>A · p.?
PRPF8
NM_006445.3:c.6854-4G>A is classified as Benign.
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, BS2 strong benign, BP4 supporting benign, BP6 supporting benign; combination = 1 stand-alone benign + 2 strong benign + 2 supporting benign, which maps to Benign.
Classification rationale
BA1BS1BS2BP4BP6
Benign
PRPF8 c.6854-4G>A
BA1 + BS1 + BS2 + BP4 + BP6
→
Benign
6
generic_acmg_combination_rules
Gene diagram
· NM_006445.3 · variants mapped to exon structure
PRPF8
NM_006445.3
Fetching transcript structure from UCSC…
Applied criteria · 5 applied · 15 assessed
Applied · 5
Strength
Supporting
Moderate
Strong
Very strong
✓
BA1
stand-alone
Benign
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 v2.1 African/African American AF = 4.72% (1177/24962 alleles32 homozygotes)gnomAD v4.1 African/African American AF = 4.79% (3597/75018 alleles
✓
BS1
strong
Benign
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 v2.1 overall AF = 0.45% (1280/282218 alleles)gnomAD v4.1 overall AF = 0.25% (4069/1614148 alleles)Exceeds 0.3% BS1 threshold defined for generic ACMG non-VCEP adjudication
✓
BS2
strong
Benign
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 v2.1: 32 homozygotes observedgnomAD v4.1: 87 homozygotes observedHomozygous state incompatible with a fully penetrant autosomal dominant retinal dystrophy
✓
BP4
supporting
Benign
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 max delta = 0.00 — no predicted donor/acceptor gain or lossLocated at c.6854-4outside the canonical splice consensus
✓
BP6
supporting
Benign
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 Variation ID: 321870classification: Benign3 clinical laboratories concur (Illumina
Assessed · not applied
Pathogenic
PVS1
NM_006445.3:c.6854-4G>A is an intronic variant located 4 bases upstream of exon 43.
PS2
No de novo observation has been reported for NM_006445.3:c.6854-4G>A in any reviewed publication or database submission.
PS3
No functional data exists for NM_006445.3:c.6854-4G>A or a systematically characterized range that includes this variant.
PS4
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.
PM1
Located in a region with substantial benign variation in population databases (AF = 4.7% in African population, 32 homozygotes in gnomAD).
PM2
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.
PM6
No de novo observation has been reported for this variant in any reviewed source.
PP1
No cosegregation data has been reported for NM_006445.3:c.6854-4G>A in any family.
PP3
Multiple lines of in silico evidence predict no pathogenic effect.
PP4
No patient phenotype data specific to this variant has been reported.
PP5
ClinVar classifies this variant as Benign (3 clinical laboratories).
Benign
BS3
No well-established in vitro or in vivo functional study has directly assessed the effect of NM_006445.3:c.6854-4G>A.
BS4
No nonsegregation data has been reported for this variant.
BP2
No observation of this variant in trans with a known pathogenic PRPF8 variant has been reported.
BP5
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.
N/A · 6
PS1 · PM5 · PP2 · 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= 0.00252083; MAF= 0.25208%, 4069/1614148 alleles, homozygotes = 87) and has highest observed frequency in the African/African American population (AF= 0.0479485; MAF= 4.79485%, 3597/75018 alleles, homozygotes = 85); grpmax FAF= 0.0466408.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.0045355; MAF= 0.45355%, 1280/282218 alleles, homozygotes = 32) and has highest observed frequency in the African/African American population (AF= 0.0471517; MAF= 4.71517%, 1177/24962 alleles, homozygotes = 32); grpmax FAF= 0.0447737.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.002551851449668802, 47/18418 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.25%
· 4069 / 1,614,148
87 hom · FAF 4.7%
87 hom · FAF 4.7%
African/African American 3597 / 75,018 |
4.8% 85 hom |
Middle Eastern 20 / 6,060 |
0.33% |
Remaining individuals 191 / 62,498 |
0.31% 2 hom |
Admixed American 173 / 60,026 |
0.29% |
South Asian 19 / 91,082 |
0.021% |
East Asian 6 / 44,882 |
0.013% |
European (non-Finnish) 63 / 1,180,038 |
0.0053% |
+ 3 not observed (European (Finnish), Amish, Ashkenazi Jewish)
gnomAD v2.1
0.45%
· 1280 / 282,218
32 hom · FAF 4.5%
32 hom · FAF 4.5%
African/African American 1177 / 24,962 |
4.7% 32 hom |
Admixed American 76 / 35,440 |
0.21% |
Remaining individuals 10 / 7,224 |
0.14% |
South Asian 5 / 30,616 |
0.016% |
East Asian 3 / 19,952 |
0.015% |
European (non-Finnish) 9 / 128,552 |
0.007% |
+ 2 not observed (Ashkenazi Jewish, European (Finnish))
gnomAD Canada 🇨🇦
0.26%
· 47 / 18,418
0 hom · FAF 3%
0 hom · FAF 3%
African/African American 40 / 1,020 |
3.9% |
Middle Eastern 1 / 144 |
0.69% |
Latino/Admixed American 3 / 838 |
0.36% |
Remaining individuals 3 / 1,136 |
0.26% |
+ 5 not observed (Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), South Asian)
ClinVar
This variant has been reported in ClinVar as Benign (3 clinical laboratories). (ClinVarID = 321870)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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