NM_006445.3:c.3299+14T>C is an intronic variant in PRPF8 located at position +14 of intron 21. The variant is present at extremely high frequency in population databases, with a grpmax filtering allele frequency of 4.48-4.65% in gnomAD and up to 4.78% in the African/African American subpopulation. This exceeds the BA1 stand-alone benign threshold of >1% by a wide margin.1 The variant has been observed in 34 homozygous individuals in gnomAD v2.1 and 87 homozygous individuals in gnomAD v4.1, which is incompatible with autosomal dominant retinitis pigmentosa caused by PRPF8. This satisfies BS2 at strong benign strength.2 SpliceAI predicts no splicing impact (max delta score = 0.01), with no predicted alterations to donor or acceptor sites, supporting a benign interpretation (BP4). No functional studies or clinical case reports were identified for this variant in the reviewed literature.3 This variant has been classified as Benign by three clinical laboratories in ClinVar (VariationID 321893), though the review status is single-submitter and does not meet the 3-star expert panel threshold required for PP5/BP6 application under the governing framework.4 Based on BA1 (stand-alone benign) alone, this variant is classified as Benign. BS1, BS2, and BP4 provide additional independent evidence supporting benign classification.5
PRPF8
Final classification
Unclassified
PRPF8 c.3299+14T>C · p.?
PRPF8
NM_006445.3:c.3299+14T>C is an intronic variant in PRPF8 located at position +14 of intron 21. The variant is present at extremely high frequency in population databases, with a grpmax filtering allele frequency of 4.48-4.65% in gnomAD and up to 4.78% in the African/African American subpopulation. This exceeds the BA1 stand-alone benign threshold of >1% by a wide margin.
Classification rationale
BA1BS1BS2BP4
Unclassified
PRPF8 c.3299+14T>C
· exon NC_000017.10
BA1 + BS1 + BS2 + BP4
→
Unclassified
Gene diagram
· NM_006445.3 · variants mapped to exon structure
PRPF8
NM_006445.3
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 17 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
BA1
stand-alone
Benign
This variant has an allele frequency far exceeding the BA1 threshold of >1%. The grpmax filtering allele frequency is 4.48% in gnomAD v2.1 (African/African American subpopulation AF = 4.74%) and 4.65% in gnomAD v4.1 (African/African American subpopulation AF = 4.78%). Additionally, 34 homozygotes are observed in gnomAD v2.1 and 87 homozygotes in gnomAD v4.1, confirming this is a common polymorphism incompatible with a highly penetrant Mendelian disorder such as PRPF8-related retinitis pigmentosa.
gnomAD v2.1 grpmax FAF = 4.48% (>> 1% BA1 threshold)gnomAD v4.1 grpmax FAF = 4.65% (>> 1% BA1 threshold)34 homozygotes in v2.1
✓
BS1
strong
Benign
The overall allele frequency exceeds the BS1 threshold of >0.3%. gnomAD v2.1 overall AF = 0.455% (1286/282376 alleles). While gnomAD v4.1 overall AF = 0.251% is below the BS1 threshold, the v2.1 frequency meets the criterion. This criterion is effectively subsumed by BA1 (stand-alone benign) given the grpmax FAF of 4.5%, but is independently met based on population frequency.
gnomAD v2.1 overall AF = 0.455% (> 0.3% BS1 threshold)
✓
BS2
strong
Benign
This variant has been observed in 34 homozygous individuals in gnomAD v2.1 and 87 homozygous individuals in gnomAD v4.1. PRPF8-related retinitis pigmentosa is inherited in an autosomal dominant manner. Observation of multiple healthy homozygous individuals for a dominant disorder is inconsistent with pathogenicity and satisfies BS2.
34 homozygotes in gnomAD v2.187 homozygotes in gnomAD v4.1Inconsistent with autosomal dominant RP
✓
BP4
supporting
Benign
Multiple lines of computational evidence support a benign interpretation. SpliceAI predicts no splicing impact for this intronic variant (max delta score = 0.01), with no predicted acceptor gain, acceptor loss, donor gain, or donor loss. REVEL and BayesDel scores are not applicable to intronic variants. The SpliceAI prediction is specifically designed to detect splice-altering variants and finds no evidence of altered splicing at this position.
SpliceAI max delta = 0.01 (no predicted splicing impact)No donor/acceptor gain or loss predicted
Assessed · not applied
Pathogenic
PS2
No de novo observation was identified in any reviewed publication or case data for NM_006445.3:c.3299+14T>C.
PS3
No functional studies were identified for NM_006445.3:c.3299+14T>C.
PS4
No case-control studies or systematic cohort evidence was identified for this variant.
PM1
This is an intronic variant at position c.3299+14, not located in a characterized functional domain or mutational hotspot.
PM2
This variant is present in gnomAD at frequencies far exceeding the PM2 threshold of <0.1%.
PM6
No de novo observation was identified in any reviewed publication or case data for NM_006445.3:c.3299+14T>C.
PP1
No segregation data was identified for this variant in any reviewed publication or case submission.
PP2
This is an intronic variant, not a missense change.
PP3
No in silico evidence supports a deleterious effect.
PP4
No specific patient phenotype data was provided for this case.
PP5
ClinVar classification is Benign, not Pathogenic/Likely Pathogenic.
Benign
BS3
No functional studies were identified demonstrating that NM_006445.3:c.3299+14T>C has no deleterious effect.
BS4
No segregation data demonstrating lack of cosegregation with disease was identified for this variant.
BP1
This is an intronic variant, not a missense change.
BP2
No evidence was identified of this variant being observed in trans with a known pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any reviewed publication or case submission.
BP5
BP5 requires observation of the variant in a case with an alternate molecular basis for disease.
BP6
ClinVar classification is Benign with review status 'criteria provided, single submitter' — not a 3-star expert panel review.
N/A · 4
PVS1 · PS1 · PM5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.00250998; MAF= 0.25100%, 4047/1612366 alleles, homozygotes = 87) and has highest observed frequency in the African/African American population (AF= 0.0477956; MAF= 4.77956%, 3584/74986 alleles, homozygotes = 85); grpmax FAF= 0.0464895.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00455421; MAF= 0.45542%, 1286/282376 alleles, homozygotes = 34) and has highest observed frequency in the African/African American population (AF= 0.0474283; MAF= 4.74283%, 1184/24964 alleles, homozygotes = 33); grpmax FAF= 0.044839.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0029335071707953064, 54/18408 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.25%
· 4047 / 1,612,366
87 hom · FAF 4.6%
87 hom · FAF 4.6%
African/African American 3584 / 74,986 |
4.8% 85 hom |
Remaining individuals 182 / 62,430 |
0.29% 1 hom |
Admixed American 171 / 60,014 |
0.28% |
Middle Eastern 17 / 6,038 |
0.28% |
South Asian 20 / 91,026 |
0.022% 1 hom |
European (non-Finnish) 73 / 1,178,438 |
0.0062% |
+ 4 not observed (European (Finnish), Amish, East Asian, Ashkenazi Jewish)
gnomAD v2.1
0.46%
· 1286 / 282,376
34 hom · FAF 4.5%
34 hom · FAF 4.5%
African/African American 1184 / 24,964 |
4.7% 33 hom |
Admixed American 75 / 35,438 |
0.21% |
Remaining individuals 11 / 7,220 |
0.15% |
South Asian 8 / 30,616 |
0.026% 1 hom |
European (non-Finnish) 8 / 128,702 |
0.0062% |
+ 3 not observed (Ashkenazi Jewish, East Asian, European (Finnish))
gnomAD Canada 🇨🇦
0.29%
· 54 / 18,408
0 hom · FAF 3%
0 hom · FAF 3%
African/African American 41 / 1,020 |
4% |
Middle Eastern 1 / 144 |
0.69% |
Latino/Admixed American 4 / 838 |
0.48% |
Remaining individuals 3 / 1,134 |
0.26% |
European (non-Finnish) 5 / 11,732 |
0.043% |
+ 4 not observed (Ashkenazi Jewish, East Asian, European (Finnish), South Asian)
COSMIC
Somatic evidence
COSMIC
In progress — evidence not uploaded yet.
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