NM_006445.3:c.5352C>T (p.Asn1784=) is a synonymous variant in PRPF8 with no predicted splicing impact (SpliceAI max delta = 0.04; BP7).1 Multiple lines of computational evidence suggest no deleterious effect, with no significant splice alteration predicted (BP4).2 The variant is present in gnomAD at appreciable frequency (v2.1: 0.089%; v4.1: 0.168%) and has been observed in the homozygous state in multiple individuals (2 homozygotes in v2.1; 5 in v4.1), supporting a benign interpretation (BS2).3 ClinVar reports this variant as Likely benign / Benign across multiple clinical testing laboratories (5 of 7 submissions), with no reputable source reporting it as pathogenic (BP6).4 No pathogenic criteria are met. Four supporting benign criteria are satisfied (BS2, BP4, BP6, BP7), satisfying the generic ACMG/AMP 2015 threshold for Likely benign (≥2 supporting benign criteria).5 No published literature was identified that specifically mentions NM_006445.3:c.5352C>T; the four PMIDs associated with the ClinVar record do not contain variant-specific evidence.
PRPF8
Final classification
Likely Benign
PRPF8 c.5352C>T · p.Asn1784=
PRPF8
NM_006445.3:c.5352C>T (p.Asn1784=) is a synonymous variant in PRPF8 with no predicted splicing impact (SpliceAI max delta = 0.04; BP7).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BS2 supporting benign, BP4 supporting benign, BP6 supporting benign, BP7 supporting benign; combination = 4 supporting benign, which maps to Likely Benign.
Classification rationale
BS2BP4BP6BP7
Likely Benign
PRPF8 c.5352C>T
BS2 + BP4 + BP6 + BP7
→
Likely Benign
Gene diagram
· NM_006445.3 · variants mapped to exon structure
PRPF8
NM_006445.3
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.00167733; MAF= 0.16773%, 2706/1613276 alleles, homozygotes = 5) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00213192; MAF= 0.21319%, 2514/1179216 alleles, homozygotes = 3); grpmax FAF= 0.00206229.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000890925; MAF= 0.08909%, 252/282852 alleles, homozygotes = 2) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00163366; MAF= 0.16337%, 211/129158 alleles, homozygotes = 1); grpmax FAF= 0.00149259.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0008142438388882857, 15/18422 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.17%
· 2706 / 1,613,276
5 hom · FAF 0.21%
5 hom · FAF 0.21%
European (non-Finnish) 2514 / 1,179,216 |
0.21% 3 hom |
Middle Eastern 9 / 6,058 |
0.15% |
Remaining individuals 61 / 62,474 |
0.098% |
South Asian 64 / 91,068 |
0.07% 1 hom |
African/African American 35 / 75,026 |
0.047% 1 hom |
Admixed American 10 / 60,026 |
0.017% |
European (Finnish) 8 / 64,022 |
0.012% |
East Asian 5 / 44,872 |
0.011% |
+ 2 not observed (Amish, Ashkenazi Jewish)
gnomAD v2.1
0.089%
· 252 / 282,852
2 hom · FAF 0.15%
2 hom · FAF 0.15%
European (non-Finnish) 211 / 129,158 |
0.16% 1 hom |
South Asian 24 / 30,616 |
0.078% 1 hom |
Remaining individuals 3 / 7,226 |
0.042% |
African/African American 6 / 24,968 |
0.024% |
Admixed American 6 / 35,440 |
0.017% |
European (Finnish) 2 / 25,124 |
0.008% |
+ 2 not observed (Ashkenazi Jewish, East Asian)
gnomAD Canada 🇨🇦
0.081%
· 15 / 18,422
0 hom
0 hom
Latino/Admixed American 1 / 838 |
0.12% |
European (non-Finnish) 13 / 11,742 |
0.11% |
South Asian 1 / 1,362 |
0.073% |
+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals)
ClinVar
This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Benign (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 196868)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
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 · 4 PMIDs not cited in assessment
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