NM_006445.3:c.1666C>T (p.Leu556=) is a synonymous variant in PRPF8, a gene associated with autosomal dominant retinitis pigmentosa. This variant is present in population databases at frequencies too high for a highly penetrant pathogenic variant: gnomAD v4.1 grpmax filtering allele frequency is 0.632%, with 3 homozygotes observed in the African/African American population (AF = 0.681%).1 SpliceAI predicts no impact on splicing (max delta score = 0.00), consistent with a synonymous variant that does not alter the gene product or create/disrupt splice sites.2 ClinVar reports this variant as Benign (2 clinical laboratories) or Likely benign (1 clinical laboratory), though review status is single-submitter level (1-star).3 This variant meets BS1 (strong benign, allele frequency >0.3%), BP4 (supporting benign, no predicted splice impact), and BP7 (supporting benign, synonymous variant with no splice effect). No pathogenic criteria are met.4
PRPF8
Final classification
Likely Benign
PRPF8 c.1666C>T · p.Leu556=
PRPF8
NM_006445.3:c.1666C>T (p.Leu556=) is a synonymous variant in PRPF8, a gene associated with autosomal dominant retinitis pigmentosa.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BS1 strong benign, BP4 supporting benign, BP7 supporting benign; combination = 1 strong benign + 2 supporting benign, which maps to Likely Benign.
Classification rationale
BS1BP4BP7
Likely Benign
PRPF8 c.1666C>T
BS1 + BP4 + BP7
→
Likely Benign
Gene diagram
· NM_006445.3 · variants mapped to exon structure
PRPF8
NM_006445.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 15 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BS1
strong
Benign
The allele frequency of this variant is greater than expected for a PRPF8-associated disorder (retinitis pigmentosa). gnomAD v4.1 grpmax filtering allele frequency is 0.632%, exceeding the BS1 threshold of >0.3%. In the African/African American population, the allele frequency is 0.681% (511/75,040 alleles) with 3 homozygotes, confirming this variant is too common to cause a highly penetrant dominant disease.
gnomAD v4.1: grpmax FAF 0.632% (>0.3% BS1 threshold)African/African American AF 0.681% with 3 homozygotes.gnomAD v2.1: grpmax FAF 0.525% (>0.3% BS1 threshold)
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splice alteration (max delta score = 0.00). As a synonymous variant without predicted splicing effects, the nucleotide substitution is not expected to alter protein sequence or function.
SpliceAI max delta = 0.00 across all categories (acceptor gainacceptor lossdonor gain
✓
BP7
supporting
Benign
NM_006445.3:c.1666C>T is a synonymous variant (p.Leu556=) for which SpliceAI predicts no impact on splicing (max delta score = 0.00). The nucleotide is observed at appreciable frequency in population databases (gnomAD v4.1: 3 homozygotes, African/African American AF = 0.681%), consistent with a lack of strong evolutionary constraint at this position.
SpliceAI max delta = 0.00no predicted creation or disruption of splice sites.gnomAD v4.1: 3 homozygotes
Assessed · not applied
Pathogenic
PS3
No functional data identified for NM_006445.3:c.1666C>T.
PS4
No case-specific prevalence data available.
PM1
This synonymous variant is not located in a statistically significant mutational hotspot (cancerhotspots.org negative).
PM2
Present in gnomAD at frequencies exceeding the PM2 threshold of <0.1%.
PP1
No cosegregation data available for this variant.
PP3
No computational evidence supports a deleterious effect.
PP4
No patient phenotype data available to assess specificity to PRPF8-associated disease (retinitis pigmentosa).
PP5
ClinVar classification for this variant is Benign, not Pathogenic.
Benign
BA1
Maximum population allele frequency (gnomAD v4.1 grpmax FAF = 0.632%) is below the BA1 threshold of >1%.
BS2
No confirmed clinical observation of this variant in a healthy adult individual for a fully penetrant dominant disorder expected at an early age.
BS3
No functional studies demonstrating a benign effect for NM_006445.3:c.1666C>T were identified.
BS4
No segregation data available.
BP2
No data on observation of this variant in trans with a known pathogenic PRPF8 variant.
BP5
No data indicating an alternate molecular basis for disease in an individual carrying this variant.
BP6
ClinVar classifies this variant as Benign, but the review status is only 'criteria provided, single submitter' (1-star).
N/A · 7
PVS1 · PS1 · PS2 · PM5 · PM6 · PP2 · BP1
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000354373; MAF= 0.03544%, 572/1614118 alleles, homozygotes = 3) and has highest observed frequency in the African/African American population (AF= 0.0068097; MAF= 0.68097%, 511/75040 alleles, homozygotes = 3); grpmax FAF= 0.00632119.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00058816; MAF= 0.05882%, 166/282236 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00614162; MAF= 0.61416%, 153/24912 alleles, homozygotes = 0); grpmax FAF= 0.00524827.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027150304083405736, 5/18416 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.035%
· 572 / 1,614,118
3 hom · FAF 0.63%
3 hom · FAF 0.63%
African/African American 511 / 75,040 |
0.68% 3 hom |
Middle Eastern 4 / 6,062 |
0.066% |
Remaining individuals 30 / 62,508 |
0.048% |
Admixed American 23 / 60,018 |
0.038% |
South Asian 3 / 91,082 |
0.0033% |
European (non-Finnish) 1 / 1,180,028 |
8.5e-05% |
+ 4 not observed (European (Finnish), Amish, East Asian, Ashkenazi Jewish)
gnomAD v2.1
0.059%
· 166 / 282,236
0 hom · FAF 0.52%
0 hom · FAF 0.52%
African/African American 153 / 24,912 |
0.61% |
Admixed American 11 / 35,426 |
0.031% |
Remaining individuals 2 / 7,212 |
0.028% |
+ 5 not observed (Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), South Asian)
gnomAD Canada 🇨🇦
0.027%
· 5 / 18,416
0 hom · FAF 0.08%
0 hom · FAF 0.08%
African/African American 3 / 1,020 |
0.29% |
Latino/Admixed American 1 / 838 |
0.12% |
Remaining individuals 1 / 1,136 |
0.088% |
+ 6 not observed (Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, European (non-Finnish), South Asian)
ClinVar
This variant has been reported in ClinVar as Benign (2 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 281806)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 1 PMID not cited in assessment
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR