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
BS2BP4BP6BP7
PRPF8
c.5352C>T
p.Asn1784=
This variant
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 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
BS2
supporting
Benign
This variant has been observed in the homozygous state in population databases: 2 homozygotes in gnomAD v2.1 and 5 homozygotes in gnomAD v4.1 including across multiple ancestry groups (European non-Finnish, African/African American, South Asian). For a gene associated with autosomal dominant retinitis pigmentosa, observation of multiple apparently healthy homozygous individuals supports a benign interpretation.
gnomAD v2.1: 2 homozygotes across 282852 allelesgnomAD v4.1: 5 homozygotes across 1
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact. SpliceAI predicts no significant splice alteration (max delta = 0.04, well below the 0.1 threshold for any predicted effect). The synonymous nature of the variant (p.Asn1784=) is consistent with no protein-level consequence.
SpliceAI max delta 0.04 — no predicted splicing impactSynonymous change with no amino acid alteration
✓
BP6
supporting
Benign
This variant is classified as Likely benign or Benign by multiple clinical testing laboratories in ClinVar (VCV000196868): 3 laboratories report Likely benign, 2 report Benign, and 1 reports Uncertain significance. The multi-laboratory consensus toward a benign interpretation, including submissions from Labcorp Genetics (Invitae), Illumina, and others, supports BP6.
ClinVar: Likely benign (3 labs)Benign (2 labs)VUS (1 lab)
✓
BP7
supporting
Benign
This is a synonymous variant (p.Asn1784=) for which SpliceAI predicts no splice site alteration (max delta score = 0.04, well below the 0.1 threshold). No cryptic splice site creation or disruption is predicted. BP7 is met as a synonymous variant with no predicted splicing impact.
Synonymous variant p.(Asn1784=)SpliceAI max delta 0.04 — no predicted splice impact
Assessed · not applied
· 5 not met · 10 not assessed
Pathogenic
PS2
No de novo data with confirmed paternity and maternity were identified for this variant.
PS3
No variant-specific functional studies were identified.
PS4
No case-control data comparing variant prevalence in PRPF8-related disease cases versus controls were identified.
PM2
This variant is present in gnomAD at appreciable frequency, exceeding the 0.1% non-VCEP PM2 threshold.
PM6
No de novo data (without confirmation of paternity and maternity) were identified for this variant.
PP1
No segregation data were identified for this variant in affected families.
PP3
Multiple lines of computational evidence do not support a deleterious effect.
PP4
No proband phenotype or clinical data were available to evaluate whether the patient's presentation is highly specific for PRPF8-related disease.
PP5
ClinVar classifies this variant as Likely benign / Benign (ClinVarID: VCV000196868), with 5 of 7 submissions reporting a benign or likely benign classification.
Benign
BA1
The maximum population allele frequency is 0.213% in the European (non-Finnish) subpopulation of gnomAD v4.1.
BS1
The maximum population allele frequency is 0.213% in the European (non-Finnish) subpopulation of gnomAD v4.1.
BS3
No well-established in vitro or in vivo functional studies demonstrating no damaging effect were identified for this specific variant.
BS4
No segregation data were available to assess lack of segregation with disease.
BP2
No phasing data were available to determine whether this variant has been observed in cis with a pathogenic variant or in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP5
No data were identified showing this variant in a case with an alternate molecular basis for disease.
N/A · 6
PVS1 · PS1 · PM1 · PM5 · 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= 0.00167733; 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