Classification rationale

BA1BP7 Benign

PRPF8 c.2409G>A

The PRPF8 NM_006445.3:c.2409G>A (p.Ala803=) variant has not been reported in ClinVar as a pathogenic germline variant and is listed there as benign.¹ This variant is common in population databases, with a highest observed allele frequency of 3.582% in gnomAD v2.1, 3.636% in gnomAD v4.1, and 3.627% in gnomAD-Canada, which is above the 1% BA1 threshold.² In silico splice prediction does not support an abnormal splicing effect, with a SpliceAI maximum delta score of 0.05.³

BA1 + BP7 → Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

3 spliceai ↗

Gene diagram · NM_006445.3 · variants mapped to exon structure

PRPF8 NM_006445.3

Fetching transcript structure from UCSC…

Applied criteria · 2 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= 0.00247129; MAF= 0.24713%, 3989/1614136 alleles, homozygotes = 56) and has highest observed frequency in the African/African American population (AF= 0.03636; MAF= 3.63600%, 2727/75000 alleles, homozygotes = 50); grpmax FAF= 0.0352217.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.00494237; MAF= 0.49424%, 1398/282860 alleles, homozygotes = 26) and has highest observed frequency in the African/African American population (AF= 0.035823; MAF= 3.58230%, 894/24956 alleles, homozygotes = 24); grpmax FAF= 0.0335152.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.00211864; MAF= 0.21186%, 39/18408 alleles, homozygotes = 1) and has highest observed frequency in the afr population (AF= 0.0362745; grpmax FAF95= 0.027053).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.25% · 3989 / 1,614,136
56 hom · FAF 3.5%

African/African American 2727 / 75,000	3.6% 50 hom
European (Finnish) 774 / 64,026	1.2% 3 hom
Remaining individuals 169 / 62,508	0.27% 2 hom
Admixed American 155 / 60,024	0.26%
Middle Eastern 3 / 6,062	0.049%
European (non-Finnish) 152 / 1,180,040	0.013%
South Asian 9 / 91,082	0.0099% 1 hom

+ 3 not observed (Amish, East Asian, Ashkenazi Jewish)

gnomAD v2.1

0.49% · 1398 / 282,860
26 hom · FAF 3.4%

African/African American 894 / 24,956	3.6% 24 hom
European (Finnish) 324 / 25,108	1.3% 1 hom
Remaining individuals 18 / 7,228	0.25% 1 hom
Admixed American 72 / 35,440	0.2%
European (non-Finnish) 89 / 129,194	0.069%
South Asian 1 / 30,616	0.0033%

+ 2 not observed (Ashkenazi Jewish, East Asian)

gnomAD Canada 🇨🇦

0.21% · 39 / 18,408
1 hom · FAF 2.7%

African/African American 37 / 1,020	3.6% 1 hom
Remaining individuals 1 / 1,138	0.088%
European (non-Finnish) 1 / 11,728	0.0085%

+ 6 not observed (Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (2 clinical laboratories). (ClinVarID = 321904)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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

20301590 ↗ Nonsyndromic Retinitis Pigmentosa Overview. CLINVAR

22234150 ↗ Clinical utility gene card for: BEST1-related dystrophies (Bestrophinopathies). CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR