About PRPF8
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PRPF8 c.2409G>A, p.(Ala803=)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 0
Benign evidence criteria: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BA1Stand alone
BA1 · stand alone
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.
BP7Supporting
BP7 · supporting
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.
Recorded classification: Benign
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BP7 supporting; combination = 1 stand-alone benign + 1 supporting benign, which maps to Benign.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
3,989 / 1,614,136 alleles
gnomAD v4.1: 3,989 / 1,614,136 alleles. Recorded AF 0.00247129. Recorded homozygote count 56.
gnomAD 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.
gnomAD-Canada
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).
SpliceAI score
0.050 maximum delta
Recorded SpliceAI maximum delta score: 0.050. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
2 reported laboratory submissions
2 Benign.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 4 not met · 15 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
In silico splice prediction does not support an abnormal splicing effect, with a SpliceAI maximum delta score of 0.05.
No criteria match.
Met · 2
BA1 Stand aloneThis 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 grpmax AF 3.582%
- gnomAD v4.1 grpmax AF 3.636%
- gnomAD-Canada grpmax AF 3.627%
Sources
BP7 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- Synonymous consequence p.(Ala803=)
- SpliceAI max delta 0.05
Sources
Not met · 4 · evaluated, threshold not reached
PS4 Available evidence does not show enrichment of this variant in affected individuals compared with controls. Instead, the variant is common in population databases, which argues against case enrichment. Details ▾Hide ▴
Evidence considered
- High population frequency across multiple reference datasets
Sources
PM1 Available evidence does not support location in a mutational hotspot or critical functional domain without benign variation. Cancer Hotspots did not identify a significant hotspot at this residue. Details ▾Hide ▴
PM2 This variant is not absent from population databases. Its allele frequency is 0.494% in gnomAD v2.1, 0.247% in gnomAD v4.1, and 0.212% in gnomAD-Canada, all above the usual rarity threshold for PM2. Details ▾Hide ▴
Evidence considered
- Observed repeatedly in large reference populations
Sources
PP3 Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.05. Details ▾Hide ▴
Not assessed · 15 · no assessment recorded
PS2 No confirmed de novo data were identified for this variant. Details ▾Hide ▴
Still missing
- De novo testing with confirmed maternity and paternity was not available.
PS3 No published functional studies specific to this variant were identified that demonstrate a damaging effect. Details ▾Hide ▴
Evidence considered
- No variant-specific functional citations were retrieved
Still missing
- Variant-specific functional assay data were not available.
Sources
PM3 No data were identified showing this variant in trans with a pathogenic variant in a recessive disorder context. Details ▾Hide ▴
Still missing
- Phase data and recessive case observations were not available.
PM6 No assumed de novo data were identified for this variant. Details ▾Hide ▴
Still missing
- Reported de novo observations without full parental confirmation were not available.
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Still missing
- Family segregation data were not available.
PP4 No phenotype-specific evidence was identified showing that the clinical presentation is highly specific for a disorder caused by this variant. Details ▾Hide ▴
Still missing
- Detailed phenotype and gene-specific diagnostic context were not available.
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. Details ▾Hide ▴
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%. Details ▾Hide ▴
Evidence considered
- Population frequency exceeds benign strong threshold and also exceeds BA1 threshold
Sources
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. Details ▾Hide ▴
Evidence considered
- 26 homozygotes in gnomAD v2.1
- 56 homozygotes in gnomAD v4.1
- 1 homozygote in gnomAD-Canada
Still missing
- Confirmed healthy adult observations in an appropriate disease context were not available.
Sources
BS3 No published functional studies specific to this variant were identified that demonstrate no damaging effect. Details ▾Hide ▴
Evidence considered
- No variant-specific benign functional evidence retrieved
Still missing
- Variant-specific well-established benign functional assay data were not available.
Sources
BS4 No segregation data were identified showing lack of segregation with disease. Details ▾Hide ▴
Still missing
- Family segregation studies were not available.
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. Details ▾Hide ▴
Still missing
- Case-level phase data were not available.
BP3 No evidence was identified that this variant is an in-frame change in a repetitive region without known function. Details ▾Hide ▴
Still missing
- Region-specific repeat annotation relevant to BP3 was not available.
BP5 No evidence was identified for an alternate molecular basis that fully explains the phenotype independently of this variant. Details ▾Hide ▴
Still missing
- Comprehensive alternative diagnosis data were not available.
BP6 ClinVar contains benign submissions for this variant, but BP6 was not applied because external assertions alone were not used as primary criterion evidence. Details ▾Hide ▴
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a synonymous change, NM_006445.3:c.2409G>A (p.Ala803=), and does not fall into the generic PVS1 null-variant categories. Available evidence therefore does not support applying PVS1. Details ▾Hide ▴
Evidence considered
- Synonymous consequence p.(Ala803=)
- Generic PVS1 scaffold did not place this variant in a null-variant bucket
Sources
PS1 N/AThis criterion applies to a different nucleotide change causing the same amino acid substitution. This variant is synonymous and does not change the amino acid. Details ▾Hide ▴
PM4 N/AThis criterion applies to protein length changes from in-frame insertions, deletions, or stop-loss variants. This variant is a synonymous substitution and does not alter protein length. Details ▾Hide ▴
PM5 N/APM5 applies to a novel missense change at a residue with a different pathogenic missense change. This variant is synonymous, and the PM5 review artifact did not support classic same-residue PM5 use. Details ▾Hide ▴
Evidence considered
- No eligible same-residue missense comparator logic for this synonymous variant
Sources
pm5_candidates
PP2 N/APP2 is used for missense variants in genes with low benign missense variation and a common missense disease mechanism. This variant is not missense. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies to missense variants in genes where truncating variants are the main disease mechanism. This variant is not missense. Details ▾Hide ▴
No further detail was recorded.
BP4 N/ABP4 is generally used for missense variants when multiple computational tools support no impact on the protein. This variant is synonymous, so splice prediction is addressed under BP7 instead. Details ▾Hide ▴
Identifiers
- Gene
- PRPF8
- Transcript
- NM_006445.3
- Coding (HGVS c.)
- NM_006445.3:c.2409G>A
- Protein (HGVS p.)
- NP_006436.3:p.(Ala803=)
- GRCh38
- chr17:1676350 C>T
- GRCh37
- chr17:1579644 C>T
- ClinVar
- 321904
Gene diagram
Every interpreted variant in PRPF8, mapped onto the exon structure of NM_006445.3. Select a row to find it on the plot.
PRPF8NM_006445.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PRPF8
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
3,989 / 1,614,136 alleles
AF 0.00247 · 56 homozygotes · FAF 0.0352
gnomAD v2.1
1,398 / 282,860 alleles
AF 0.00494 · 26 homozygotes · FAF 0.0335
gnomAD-Canada v1.0
39 / 18,408 alleles
AF 0.00212 · 1 homozygotes · FAF 0.0271
By genetic ancestry
gnomAD v4.1
AF 0.0025 · 3989 / 1,614,136 alleles · 56 hom · FAF 0.035
| African/African American2727 / 75,000 | 0.03650 hom |
| European (Finnish)774 / 64,026 | 0.0123 hom |
| Remaining individuals169 / 62,508 | 0.00272 hom |
| Admixed American155 / 60,024 | 0.0026 |
| Middle Eastern3 / 6,062 | 0.00049 |
| European (non-Finnish)152 / 1,180,040 | 0.00013 |
| South Asian9 / 91,082 | 9.9e-051 hom |
0 alternate alleles recorded in 3 other groups: Amish, East Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.0049 · 1398 / 282,860 alleles · 26 hom · FAF 0.034
| African/African American894 / 24,956 | 0.03624 hom |
| European (Finnish)324 / 25,108 | 0.0131 hom |
| Remaining individuals18 / 7,228 | 0.00251 hom |
| Admixed American72 / 35,440 | 0.002 |
| European (non-Finnish)89 / 129,194 | 0.00069 |
| South Asian1 / 30,616 | 3.3e-05 |
0 alternate alleles recorded in 2 other groups: Ashkenazi Jewish, East Asian.
gnomAD-Canada
AF 0.0021 · 39 / 18,408 alleles · 1 hom · FAF 0.027
| afr37 / 1,020 | 0.0361 hom |
| oth1 / 1,138 | 0.00088 |
| nfe1 / 11,728 | 8.5e-05 |
0 alternate alleles recorded in 6 other groups: amr, asj, eas, fin, mid, sas.
Statements
gnomAD 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.
gnomAD 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.
gnomAD-Canada
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).
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP7 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- Synonymous consequence p.(Ala803=)
- SpliceAI max delta 0.05
Sources
PP3 Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.05. Details ▾Hide ▴
BP4 N/ABP4 is generally used for missense variants when multiple computational tools support no impact on the protein. This variant is synonymous, so splice prediction is addressed under BP7 instead. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).
5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 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.Richards S et al. · 2015No paper-specific finding is recorded.
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PMID 26666451 ↗In Vivo CRISPR/Cas9 Gene Editing Corrects Retinal Dystrophy in the S334ter-3 Rat Model of Autosomal Dominant Retinitis Pigmentosa.Bakondi B et al. · 2016No paper-specific finding is recorded.
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PMID 20301590 ↗Nonsyndromic Retinitis Pigmentosa Overview.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 22234150 ↗Clinical utility gene card for: BEST1-related dystrophies (Bestrophinopathies).Ramsden SC et al. · 2012No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
3,989 / 1,614,136 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.050
Open source ↗
ClinVar
2 Benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/321904/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-1579644-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-1676350-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-1676350-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006445.3%3Ac.2409…
- OncoKB ↗www.oncokb.org/gene/PRPF8/A803=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PRPF8+c.2409G%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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.
gnomAD 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.
gnomAD-Canada
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).
ClinVar
This variant has been reported in ClinVar as Benign (2 clinical laboratories). (ClinVarID = 321904)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.