NM_006445.3:c.1929C>T (p.Gly643=) is a synonymous variant in PRPF8 with no predicted splice impact (SpliceAI max delta 0.10).1 This variant is present in gnomAD v2.1 at an overall allele frequency of 0.059% (167/282,738 alleles) with a grpmax filtering allele frequency of 0.524% in the African/African American population, exceeding the 0.3% threshold for BS1.2 In gnomAD v4.1, the variant is observed at an overall frequency of 0.035% (568/1,613,942 alleles) with a grpmax FAF of 0.629% and 3 homozygous individuals, confirming it is established in the general population at frequencies inconsistent with a fully penetrant pathogenic variant.3 ClinVar classifies this variant as Benign (2 clinical laboratories) and Likely benign (1 clinical laboratory), with a 2-star review status (criteria provided, multiple submitters, no conflicts). Three independent clinical laboratories have reached a benign or likely benign conclusion.4 Based on the generic ACMG/AMP 2015 framework, the variant meets BS1 (supporting benign), BS2 (supporting benign), BP4 (supporting benign), and BP7 (supporting benign), totaling 4 supporting benign criteria, consistent with a classification of Likely Benign.5
PRPF8
Final classification
Unclassified
PRPF8 c.1929C>T · p.Gly643=
PRPF8
NM_006445.3:c.1929C>T (p.Gly643=) is a synonymous variant in PRPF8 with no predicted splice impact (SpliceAI max delta 0.10).
Classification rationale
BS1BS2BP4BP7
Unclassified
PRPF8 c.1929C>T
· exon NC_000017.10
BS1 + BS2 + BP4 + BP7
→
Unclassified
Gene diagram
· NM_006445.3 · variants mapped to exon structure
PRPF8
NM_006445.3
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 16 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
BS1
supporting
Benign
The grpmax filtering allele frequency exceeds the 0.3% threshold for BS1 (0.524% in gnomAD v2.1; 0.629% in gnomAD v4.1), and 3 homozygotes are observed in v4.1, indicating this variant is more common than expected for a fully penetrant dominant disorder.
gnomAD v2.1: grpmax FAF 0.524% (AFR)gnomAD v4.1: grpmax FAF 0.629% (AFR)3 homozygotes.
✓
BS2
supporting
Benign
Three homozygous individuals for this variant are observed in gnomAD v4.1 (total 568 alleles, 3 homozygotes). For a gene associated with autosomal dominant retinitis pigmentosa, the presence of homozygous individuals in a population database is inconsistent with a highly penetrant pathogenic variant.
gnomAD v4.1: 3 homozygous individuals observedconsistent with benign variation.
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on gene product. SpliceAI predicts no significant splice alteration (max delta 0.10, below the 0.2 threshold), and the variant is synonymous with no amino acid change. REVEL and BayesDel are not applicable.
SpliceAI max delta 0.10 (no predicted splice impact)synonymous variant with no amino acid alteration.
✓
BP7
supporting
Benign
This is a synonymous variant (p.Gly643=) at a nucleotide position that is not highly conserved, with SpliceAI predicting no significant splice impact (max delta 0.10). The high population frequency in the African population (AF 0.62–0.68%) with 3 homozygotes in gnomAD v4.1 further supports that this nucleotide position tolerates variation.
Synonymous variant (p.Gly643=)SpliceAI max delta 0.10 confirming no cryptic splice site creationhigh population frequency indicates nucleotide not under strong selective constraint.
Assessed · not applied
Pathogenic
PS2
No de novo confirmation data are available for this variant.
PS3
No variant-specific functional data were identified for NM_006445.3:c.1929C>T.
PS4
No case-control or prevalence data are available comparing affected versus unaffected individuals for this variant.
PM1
No statistically significant hotspot was identified at this residue in cancerhotspots.org, and while PRPF8 encodes a core spliceosome component, there is no evidence that this synonymous position falls within a critical functional domain where synonymous changes are known to be pathogenic.
PM2
While the overall gnomAD allele frequency (0.059% v2.1, 0.035% v4.1) is below the 0.1% PM2 threshold, the grpmax filtering allele frequency is elevated (0.524% v2.1, 0.629% v4.1) with 3 homozygotes observed in v4.1, indicating this variant is well-established in certain populations and does not meet the intent of PM2 as a rare variant criterion.
PM6
No de novo observation has been reported for this variant.
PP1
No co-segregation data are available for this variant.
PP3
Multiple computational predictors do not support a deleterious effect.
PP4
No proband phenotype or family history data are available for evaluation.
PP5
ClinVar reports this variant as Benign/Likely benign (2-star, criteria provided, multiple submitters, no conflicts).
Benign
BA1
The overall gnomAD allele frequency (0.059% v2.1, 0.035% v4.1) and grpmax filtering allele frequency (0.524% v2.1, 0.629% v4.1) are both below the 1% BA1 threshold.
BS3
No in vitro or in vivo functional studies demonstrating a benign effect were identified for this variant.
BS4
No family segregation data demonstrating lack of co-segregation with disease are available.
BP2
No observation of this variant in trans with a known pathogenic variant has been reported.
BP5
No evidence that an alternative molecular basis for disease has been identified in a case carrying this variant.
BP6
ClinVar reports this variant as Benign/Likely benign with a 2-star review status (criteria provided, multiple submitters, no conflicts), but this does not meet the 3-star expert panel threshold required for BP6 application under the generic ACMG framework.
N/A · 5
PVS1 · PS1 · PM5 · PP2 · BP1
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000351933; MAF= 0.03519%, 568/1613942 alleles, homozygotes = 3) and has highest observed frequency in the African/African American population (AF= 0.00677785; MAF= 0.67779%, 508/74950 alleles, homozygotes = 3); grpmax FAF= 0.0062901.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000590653; MAF= 0.05907%, 167/282738 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.0061773; MAF= 0.61773%, 154/24930 alleles, homozygotes = 0); grpmax FAF= 0.00523856.
🇨🇦 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%
· 568 / 1,613,942
3 hom · FAF 0.63%
3 hom · FAF 0.63%
African/African American 508 / 74,950 |
0.68% 3 hom |
Middle Eastern 4 / 6,060 |
0.066% |
Remaining individuals 30 / 62,506 |
0.048% |
Admixed American 23 / 59,982 |
0.038% |
South Asian 2 / 91,076 |
0.0022% |
European (non-Finnish) 1 / 1,180,000 |
8.5e-05% |
+ 4 not observed (European (Finnish), Amish, East Asian, Ashkenazi Jewish)
gnomAD v2.1
0.059%
· 167 / 282,738
0 hom · FAF 0.52%
0 hom · FAF 0.52%
African/African American 154 / 24,930 |
0.62% |
Admixed American 11 / 35,432 |
0.031% |
Remaining individuals 2 / 7,224 |
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%
indel · split
African/African American 3 / 1,020 |
0.29% |
Latino/Admixed American 1 / 838 |
0.12% |
Remaining individuals 1 / 1,138 |
0.088% |
+ 6 not observed (Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, European (non-Finnish), South Asian)
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
In progress — evidence not uploaded yet.
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