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 applied · 19 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

BA1 stand-alone Benign

This variant is too common for a pathogenic germline variant. The highest observed population frequency is 3.582% in African/African American individuals in gnomAD v2.1, 3.636% in African/African American individuals in gnomAD v4.1, and 3.627% in the afr population in gnomAD-Canada, all above the 1% BA1 threshold.

gnomAD v2.1 grpmax AF 3.582%gnomAD v4.1 grpmax AF 3.636%gnomAD-Canada grpmax AF 3.627%

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP7 supporting Benign

This is a synonymous variant, NM_006445.3:c.2409G>A (p.Ala803=), and available splice prediction does not support an effect on splicing. SpliceAI shows a maximum delta score of 0.05, consistent with no significant splice impact.

Synonymous consequence p.(Ala803=)SpliceAI max delta 0.05

clinvar ↗spliceai ↗

Assessed · not applied

Pathogenic

PS2 No confirmed de novo data were identified for this variant.

PS3 No published functional studies specific to this variant were identified that demonstrate a damaging effect.

PS4 Available evidence does not show enrichment of this variant in affected individuals compared with controls.

PM1 Available evidence does not support location in a mutational hotspot or critical functional domain without benign variation.

PM2 This variant is not absent from population databases.

PM3 No data were identified showing this variant in trans with a pathogenic variant in a recessive disorder context.

PM6 No assumed de novo data were identified for this variant.

PP1 No segregation data were identified for this variant.

PP3 Available computational evidence does not support a deleterious effect.

PP4 No phenotype-specific evidence was identified showing that the clinical presentation is highly specific for a disorder caused by this variant.

PP5 Although ClinVar contains benign submissions for this variant, PP5 is not applied because this is not pathogenic supportive evidence and external assertions alone were not used as primary criterion evidence.

Benign

BS1 The population frequency is above the BS1 threshold, but BS1 was not additionally applied because BA1 is already met based on a frequency above 1%.

BS2 This variant is observed with homozygotes in population databases, which is reassuring, but phenotype-free adult observations and penetrance context were not established well enough here to apply BS2 independently.

BS3 No published functional studies specific to this variant were identified that demonstrate no damaging effect.

BS4 No segregation data were identified showing lack of segregation with disease.

BP2 No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis for any disorder context.

BP3 No evidence was identified that this variant is an in-frame change in a repetitive region without known function.

BP5 No evidence was identified for an alternate molecular basis that fully explains the phenotype independently of this variant.

BP6 ClinVar contains benign submissions for this variant, but BP6 was not applied because external assertions alone were not used as primary criterion evidence.

N/A · 7 PVS1 · PS1 · PM4 · PM5 · PP2 · BP1 · BP4

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

Re-run this variant?