NM_006445.3:c.2631G>A is a synonymous variant (p.Ala877=) in PRPF8 with SpliceAI max delta = 0.00, predicting no splicing impact, satisfying BP7.1 Multiple lines of computational evidence, including SpliceAI (max delta = 0.00) and the synonymous nature of the variant, show no predicted damaging effect, satisfying BP4.2 This variant is present at a population frequency of 0.45% (1273/282848 alleles) in gnomAD v2.1, exceeding the 0.3% threshold for BS1.3 The variant has been observed in the homozygous state in 33 individuals in gnomAD v2.1 and 86 individuals in gnomAD v4.1, satisfying BS2.4 This variant has been reported in ClinVar as Benign by three clinical laboratories (ClinVar Variation ID: 321901), consistent with all benign criteria assessed.5 No published literature identifies NM_006445.3:c.2631G>A in association with disease; all papers reviewed discuss the gene at a general level or address unrelated genes and variants. The variant is classified as Likely Benign under the generic ACMG/AMP 2015 framework based on BS1, BS2, BP4, and BP7 (4 supporting benign criteria). The high population frequency (4.68% in African/African American) and numerous homozygotes (up to 86 in v4.1) strongly support that this is a benign polymorphism.6
PRPF8
Final classification
Likely Benign
PRPF8 c.2631G>A · p.Ala877=
PRPF8
NM_006445.3:c.2631G>A is a synonymous variant (p.Ala877=) in PRPF8 with SpliceAI max delta = 0.00, predicting no splicing impact, satisfying 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: BS1 supporting benign, BS2 supporting benign, BP4 supporting benign, BP7 supporting benign; combination = 4 supporting benign, which maps to Likely Benign.
Classification rationale
BS1BS2BP4BP7
Likely Benign
PRPF8 c.2631G>A
BS1 + BS2 + 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 · 4 applied · 16 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
BS1
supporting
Benign
This variant is present at a population frequency exceeding 0.3% in gnomAD v2.1 (AF=0.45%, 1273/282848 alleles). Although gnomAD v4.1 shows a slightly lower overall frequency (AF=0.25%), the v2.1 data with 1273 allele observations including 33 homozygotes supports BS1. The variant is particularly common in the African/African American population (AF=4.68% v2.1, 4.75% v4.1).
gnomAD v2.1 overall AF=0.45% (>0.3% threshold)1273 alleles observed33 homozygotes
✓
BS2
supporting
Benign
This variant has been observed in the homozygous state in 33 individuals in gnomAD v2.1 and 86 individuals in gnomAD v4.1, indicating it is well-tolerated in biallelic form and inconsistent with causing a fully penetrant dominant or recessive disorder.
33 homozygotes in gnomAD v2.186 homozygotes in gnomAD v4.1
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact: SpliceAI predicts no splicing impact (max delta = 0.00). REVEL and BayesDel scores are not available for this synonymous change. The variant is synonymous and does not alter the encoded amino acid.
SpliceAI max delta = 0.00 (no splice impact)synonymous variant with no amino acid changeno in silico predictors suggest a damaging effect
✓
BP7
supporting
Benign
This is a synonymous variant (p.Ala877=) for which SpliceAI predicts no impact on splicing (max delta = 0.00). The nucleotide substitution does not create a novel splice site nor disrupt a splice consensus sequence.
Synonymous variant (p.Ala877=)SpliceAI max delta = 0.00no predicted splice impact
Assessed · not applied
Pathogenic
PS2
No de novo observation reported for this variant.
PS3
No functional studies have been performed on this specific synonymous variant.
PS4
No evidence of enrichment in affected individuals versus controls.
PM1
This synonymous variant does not lie in a statistically significant mutational hotspot (cancerhotspots.org), nor is there evidence that this residue position disrupts a critical functional domain.
PM2
This variant is present in gnomAD at frequencies exceeding the PM2 threshold of <0.1%: v2.1 overall AF=0.45% (1273/282848 alleles), v4.1 overall AF=0.25% (4034/1614020 alleles).
PM6
No de novo observation has been reported for this variant in any individual with disease.
PP1
No segregation data are available for this variant in affected families.
PP3
In silico predictors are neutral: SpliceAI max delta = 0.00 predicts no splicing impact.
PP4
No specific phenotypic data link this variant to disease.
PP5
ClinVar classification is Benign (not Pathogenic).
Benign
BA1
The overall allele frequency in gnomAD v2.1 is 0.45% and in v4.1 is 0.25%, both below the BA1 threshold of >1%.
BS3
No well-established in vitro or in vivo functional studies have been performed on this specific synonymous variant demonstrating no damaging effect.
BS4
No segregation data are available showing lack of cosegregation with disease in affected families.
BP2
No evidence that this variant has been observed in trans with a known pathogenic variant for a fully penetrant dominant disorder.
BP5
No evidence that this variant has been identified in a case with an alternative molecular basis for disease.
BP6
ClinVar classifies this variant as Benign (3 clinical laboratories), but the review status is 'criteria provided, single submitter' (1-star).
N/A · 5
PVS1 · PS1 · 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= 0.00249935; MAF= 0.24993%, 4034/1614020 alleles, homozygotes = 86) and has highest observed frequency in the African/African American population (AF= 0.0474661; MAF= 4.74661%, 3561/75022 alleles, homozygotes = 84); grpmax FAF= 0.0461652.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00450065; MAF= 0.45007%, 1273/282848 alleles, homozygotes = 33) and has highest observed frequency in the African/African American population (AF= 0.0468211; MAF= 4.68211%, 1168/24946 alleles, homozygotes = 32); grpmax FAF= 0.0444801.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0029319144315343684, 54/18418 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.25%
· 4034 / 1,614,020
86 hom · FAF 4.6%
86 hom · FAF 4.6%
African/African American 3561 / 75,022 |
4.7% 84 hom |
Remaining individuals 183 / 62,488 |
0.29% 1 hom |
Middle Eastern 17 / 5,980 |
0.28% |
Admixed American 169 / 60,014 |
0.28% |
South Asian 20 / 91,064 |
0.022% 1 hom |
European (non-Finnish) 84 / 1,180,028 |
0.0071% |
+ 4 not observed (European (Finnish), Amish, East Asian, Ashkenazi Jewish)
gnomAD v2.1
0.45%
· 1273 / 282,848
33 hom · FAF 4.4%
33 hom · FAF 4.4%
African/African American 1168 / 24,946 |
4.7% 32 hom |
Admixed American 76 / 35,438 |
0.21% |
Remaining individuals 11 / 7,228 |
0.15% |
South Asian 8 / 30,616 |
0.026% 1 hom |
European (non-Finnish) 10 / 129,178 |
0.0077% |
+ 3 not observed (Ashkenazi Jewish, East Asian, European (Finnish))
gnomAD Canada 🇨🇦
0.29%
· 54 / 18,418
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 / 1,138 |
0.26% |
European (non-Finnish) 5 / 11,738 |
0.043% |
+ 4 not observed (Ashkenazi Jewish, East Asian, European (Finnish), South Asian)
ClinVar
This variant has been reported in ClinVar as Benign (3 clinical laboratories). (ClinVarID = 321901)
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 · 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