About PRPF8
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PRPF8 c.6247C>T, p.(Leu2083=)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely 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: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BS1Strong
BS1 · strong
Allele frequency exceeds the 0.3% BS1 threshold for a disorder-causing variant: 0.469% in gnomAD v2.1 (1327/282876 alleles, 32 homozygotes) and 0.267% in gnomAD v4.1 (89 homozygotes), with ~4.8% frequency in the African/African American subpopulation, indicating the variant is too common to cause a rare dominant retinopathy.
BP6Supporting
BP6 · supporting
ClinVar, a reputable source, reports this variant as Benign from three clinical laboratories (ClinVarID 321876); the underlying laboratory evidence is not available for independent evaluation, consistent with BP6.
BP7Supporting
BP7 · supporting
The variant is synonymous (p.Leu2083=) and SpliceAI predicts no impact on splicing (max delta 0.01); no evidence indicates the nucleotide is highly conserved or that the change disrupts function.
Recorded classification: Likely 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: BS1 strong benign, BP6 supporting benign, BP7 supporting benign; combination = 1 strong benign + 2 supporting benign, which maps to Likely 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
4,309 / 1,614,142 alleles
gnomAD v4.1: 4,309 / 1,614,142 alleles. Recorded AF 0.00266953. Recorded homozygote count 89.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.0046911; MAF= 0.46911%, 1327/282876 alleles, homozygotes = 32) and has highest observed frequency in the African/African American population (AF= 0.0480369; MAF= 4.80369%, 1199/24960 alleles, homozygotes = 31); grpmax FAF= 0.0458484.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0029862091432294497, 55/18418 alleles, homozygotes = 0).
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
3 reported laboratory submissions
3 Benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
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.
29 criteria with recorded statuses: 3 met · 17 not met · 0 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The variant is a synonymous change (p.Leu2083=) with no predicted splice impact (SpliceAI max delta 0.01), so no loss-of-function or missense mechanism is supported.
It is present in gnomAD at 0.469% (v2.1) and 0.267% (v4.1) allele frequency with 32 and 89 homozygotes respectively, exceeding the 0.3% BS1 threshold for a disorder-causing variant in a rare dominant retinopathy gene (BS1, strong benign).
ClinVar reports the variant as Benign from three clinical laboratories, a reputable-source benign assertion applied at supporting strength (BP6).
As a synonymous variant with no splice impact and no evidence of high conservation, BP7 is applied at supporting strength.
No pathogenic criterion is met: PVS1, PS1, PM1, PM5, PP2, BP1, BP3, PM3, and PM4 are structurally inapplicable to a synonymous substitution, and no de novo, segregation, functional, case-prevalence, or phenotype evidence exists.
Per the generic ACMG/AMP 2015 combination rules, one strong benign criterion plus supporting benign criteria (BS1 + BP6 + BP7) supports Likely Benign.
No criteria match.
Met · 3
BS1 StrongAllele frequency exceeds the 0.3% BS1 threshold for a disorder-causing variant: 0.469% in gnomAD v2.1 (1327/282876 alleles, 32 homozygotes) and 0.267% in gnomAD v4.1 (89 homozygotes), with ~4.8% frequency in the African/African American subpopulation, indicating the variant is too common to cause a rare dominant retinopathy. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.469% >0.3% threshold
- 32 homozygotes
- gnomAD v4.1 AF=0.267%
- 89 homozygotes
- AFR subpopulation AF ~4.8% in both versions
Sources
BP6 SupportingClinVar, a reputable source, reports this variant as Benign from three clinical laboratories (ClinVarID 321876); the underlying laboratory evidence is not available for independent evaluation, consistent with BP6. Details ▾Hide ▴
Evidence considered
- ClinVar classification Benign
- 3 clinical laboratory submissions (Illumina
- ARUP
- Labcorp)
- all single-submitter review
- no expert panel submission
Still missing
- ClinVar submissions are 1-star (criteria provided
- single submitter) without expert panel review
- lab criteria not disclosed
Sources
BP7 SupportingThe variant is synonymous (p.Leu2083=) and SpliceAI predicts no impact on splicing (max delta 0.01); no evidence indicates the nucleotide is highly conserved or that the change disrupts function. Details ▾Hide ▴
Evidence considered
- Synonymous consequence p.Leu2083=
- SpliceAI max delta 0.01 (no acceptor/donor gain or loss)
Still missing
- Nucleotide conservation score (e.g.
- PhyloP/GERP) not directly available in the case packet
Sources
Not met · 17 · evaluated, threshold not reached
PS2 No de novo occurrence of this variant has been reported in any source reviewed. Details ▾Hide ▴
Evidence considered
- No de novo report for NM_006445.3:c.6247C>T identified in case packet
Still missing
- No parental testing or de novo observation data available
PS3 No variant-specific or systematic functional characterization of this variant exists in the reviewed literature; functional criteria cannot be applied. Details ▾Hide ▴
Evidence considered
- No functional studies of NM_006445.3:c.6247C>T identified
- all reviewed papers lack the variant
Still missing
- No functional assay data for this synonymous variant
PS4 No case-control or prevalence data indicate an enrichment of this variant in affected individuals. Details ▾Hide ▴
Evidence considered
- No case observations of NM_006445.3:c.6247C>T in the reviewed literature
- ClinVar lists the variant as Benign
PM2 Allele frequency far exceeds the PM2 threshold: 0.469% in gnomAD v2.1 and 0.267% in gnomAD v4.1, with 32 and 89 homozygotes respectively, so absence from population databases is not supported. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.469% (1327/282876 alleles
- 32 homozygotes)
- gnomAD v4.1 AF=0.267% (4309/1614142 alleles
- 89 homozygotes)
- AFR subpopulation AF ~4.8% in both versions
Sources
PM6 No de novo report (confirmed or assumed) for this variant was identified in any reviewed source. Details ▾Hide ▴
Evidence considered
- No de novo observation of NM_006445.3:c.6247C>T found
Still missing
- No de novo case report available
PP1 No co-segregation data in affected family members is available for this variant. Details ▾Hide ▴
Evidence considered
- No segregation studies reported for NM_006445.3:c.6247C>T
Still missing
- No family segregation data available
PP3 Computational evidence does not support a deleterious effect: SpliceAI predicts no splice impact (max delta 0.01) and no missense predictors apply to a synonymous variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01 (no significant splice impact)
- REVEL and BayesDel not available for synonymous variant
Sources
PP4 No phenotype or family history data specific to this variant was provided; the criterion cannot be applied. Details ▾Hide ▴
Evidence considered
- No patient phenotype information available for NM_006445.3:c.6247C>T
Still missing
- No clinical phenotype data associated with this variant
PP5 Reputable sources report the variant as Benign rather than pathogenic, and no expert-panel pathogenic assertion exists; PP5 is not supported. Details ▾Hide ▴
Evidence considered
- ClinVar classification is Benign (3 clinical laboratories
- single-submitter review)
- no expert panel submission
Sources
BA1 Overall allele frequency (0.469% in gnomAD v2.1) is below the 1% stand-alone benign threshold; the AFR subpopulation frequency (~4.8%) is high but does not meet BA1 at the population level. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 total AF=0.469% (<1%)
- gnomAD v4.1 total AF=0.267% (<1%)
- grpmax FAF 0.0458 (v2.1) and 0.0476 (v4.1)
Sources
BS2 Population database observations (including homozygotes) are not verified healthy-adult observations with full penetrance expected at an early age for PRPF8-associated dominant disease; BS2 is not strictly met, though BS1 already captures the frequency evidence. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 32 homozygotes and v4.1 89 homozygotes in general population cohorts
- but no phenotype-verified healthy adult data
Still missing
- No verified healthy-adult phenotype data for carriers
Sources
BS3 No well-established functional studies demonstrating absence of damaging effect on protein function or splicing are available for this variant. Details ▾Hide ▴
Evidence considered
- No functional assay data for NM_006445.3:c.6247C>T in the reviewed literature
Still missing
- No functional studies available
BS4 No segregation data showing lack of segregation in affected family members is available. Details ▾Hide ▴
Evidence considered
- No family segregation data reported for NM_006445.3:c.6247C>T
Still missing
- No segregation data available
BP2 No observation of the variant in trans with a pathogenic variant (or in cis with a pathogenic variant) is documented. Details ▾Hide ▴
Evidence considered
- No allele-phase data with a pathogenic PRPF8 variant available
Still missing
- No phasing/genotype context data
BP4 Only a single computational line (SpliceAI max delta 0.01) is available; multiple independent lines of computational evidence of no impact are not met, and missense predictors do not apply to a synonymous variant (BP7 covers this variant type). Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01 predicts no splice impact
- REVEL/BayesDel/HCI prior not available for synonymous variant
Still missing
- Only one computational predictor available
Sources
BP5 No documented alternate molecular basis of disease in a case carrying this variant is available. Details ▾Hide ▴
Evidence considered
- No case-level alternate-etiology data for NM_006445.3:c.6247C>T
PS5 Reputable sources report the variant as Benign, not pathogenic; no pathogenic assertion exists to support PS5. Details ▾Hide ▴
Evidence considered
- ClinVar classifies NM_006445.3:c.6247C>T as Benign (3 clinical laboratories
- ClinVarID 321876)
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ASynonymous variant (p.Leu2083=); it is not a nonsense, frameshift, or canonical +/-1,2 splice variant, so the generic PVS1 null-variant framework does not apply. Details ▾Hide ▴
Evidence considered
- Variant bucket classified as 'other'
- apply_generic_pvs1_framework=false
- gene-level LoF context exists for PRPF8 but variant type is not eligible
Sources
pvs1_gene_contextpvs1_variant_assessment
PS1 N/ASynonymous variant with no amino acid change, so no same-residue pathogenic missense comparator can exist. Details ▾Hide ▴
No further detail was recorded.
PM1 N/ASynonymous variant; PM1 requires a missense alteration within a critical functional domain or hotspot, and no amino acid substitution occurs. Details ▾Hide ▴
Evidence considered
- Variant is synonymous (p.Leu2083=)
- no hotspot or domain-disrupting amino acid change
PM3 N/ASkipped per task instructions: PM3 concerns recessive disease with a pathogenic variant in trans and is trivially not applicable to this autosomal dominant context. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped per task instructions: PM4 concerns protein length changes and is trivially not applicable to a synonymous substitution. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ASynonymous variant with no missense change; no same-residue pathogenic missense comparator is possible, and the PM5 candidate harvest found no candidates. Details ▾Hide ▴
Evidence considered
- pm5_candidates.json: candidate_summary total_candidates_seen=0
- pm5_mode=unknown
- residue context not parseable for a synonymous consequence
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation; this variant is synonymous. Details ▾Hide ▴
Evidence considered
- Variant is synonymous (p.Leu2083=)
BP1 N/ABP1 applies to missense variants in genes for which only truncating variants cause disease; this is a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant is synonymous (p.Leu2083=)
BP3 N/ASkipped per task instructions: BP3 concerns in-frame insertions/deletions and is trivially not applicable to a single-nucleotide substitution. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- PRPF8
- Transcript
- NM_006445.3
- Coding (HGVS c.)
- NM_006445.3:c.6247C>T
- Protein (HGVS p.)
- NP_006436.3:p.(Leu2083=)
- GRCh38
- chr17:1653664 G>A
- GRCh37
- chr17:1556958 G>A
- ClinVar
- 321876
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
4,309 / 1,614,142 alleles
AF 0.00267 · 89 homozygotes · FAF 0.0476
gnomAD v2.1
1,327 / 282,876 alleles
AF 0.00469 · 32 homozygotes · FAF 0.0458
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.0027 · 4309 / 1,614,142 alleles · 89 hom · FAF 0.048
| African/African American3673 / 75,010 | 0.04986 hom |
| Middle Eastern21 / 6,062 | 0.0035 |
| Admixed American197 / 60,008 | 0.0033 |
| Remaining individuals201 / 62,510 | 0.00322 hom |
| South Asian24 / 91,082 | 0.000261 hom |
| European (non-Finnish)192 / 1,180,036 | 0.00016 |
| East Asian1 / 44,878 | 2.2e-05 |
0 alternate alleles recorded in 3 other groups: European (Finnish), Amish, Ashkenazi Jewish.
gnomAD v2.1
AF 0.0047 · 1327 / 282,876 alleles · 32 hom · FAF 0.046
| African/African American1199 / 24,960 | 0.04831 hom |
| Admixed American88 / 35,440 | 0.0025 |
| Remaining individuals11 / 7,228 | 0.0015 |
| South Asian9 / 30,616 | 0.000291 hom |
| European (non-Finnish)20 / 129,192 | 0.00015 |
0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, East Asian, European (Finnish).
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00266953; MAF= 0.26695%, 4309/1614142 alleles, homozygotes = 89) and has highest observed frequency in the African/African American population (AF= 0.0489668; MAF= 4.89668%, 3673/75010 alleles, homozygotes = 86); grpmax FAF= 0.0476449.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.0046911; MAF= 0.46911%, 1327/282876 alleles, homozygotes = 32) and has highest observed frequency in the African/African American population (AF= 0.0480369; MAF= 4.80369%, 1199/24960 alleles, homozygotes = 31); grpmax FAF= 0.0458484.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0029862091432294497, 55/18418 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP7 SupportingThe variant is synonymous (p.Leu2083=) and SpliceAI predicts no impact on splicing (max delta 0.01); no evidence indicates the nucleotide is highly conserved or that the change disrupts function. Details ▾Hide ▴
Evidence considered
- Synonymous consequence p.Leu2083=
- SpliceAI max delta 0.01 (no acceptor/donor gain or loss)
Still missing
- Nucleotide conservation score (e.g.
- PhyloP/GERP) not directly available in the case packet
Sources
PP3 Computational evidence does not support a deleterious effect: SpliceAI predicts no splice impact (max delta 0.01) and no missense predictors apply to a synonymous variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01 (no significant splice impact)
- REVEL and BayesDel not available for synonymous variant
Sources
BP4 Only a single computational line (SpliceAI max delta 0.01) is available; multiple independent lines of computational evidence of no impact are not met, and missense predictors do not apply to a synonymous variant (BP7 covers this variant type). Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01 predicts no splice impact
- REVEL/BayesDel/HCI prior not available for synonymous variant
Still missing
- Only one computational predictor available
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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. · 2015Presents the ACMG/AMP 2015 standards and guidelines for sequence variant interpretation at the framework level. NM_006445.3:c.6247C>T is not mentioned.Does not name this variant
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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. · 2016Reports in vivo CRISPR/Cas9 ablation of the dominant rhodopsin S334ter allele in a rat model of autosomal dominant retinitis pigmentosa. NM_006445.3:c.6247C>T in PRPF8 is not mentioned.Does not name this variant
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PMID 20301590 ↗Nonsyndromic Retinitis Pigmentosa Overview.Adam MP et al. · 1993GeneReviews overview of nonsyndromic retinitis pigmentosa at the disease level; no full text or abstract was available in the case packet to verify variant content. NM_006445.3:c.6247C>T was not confirmed in this source.Does not name this variant
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PMID 22234150 ↗Clinical utility gene card for: BEST1-related dystrophies (Bestrophinopathies).Ramsden SC et al. · 2012Clinical utility gene card describing BEST1-related dystrophies (Bestrophinopathies). NM_006445.3:c.6247C>T in PRPF8 is not mentioned.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Sherloc: a methodology paper refining the ACMG-AMP variant classification criteria; no full text or abstract was available in the case packet. NM_006445.3:c.6247C>T was not confirmed in this source.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
4,309 / 1,614,142 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
3 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/321876/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-1556958-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-1653664-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-1653664-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006445.3%3Ac.6247…
- OncoKB ↗www.oncokb.org/gene/PRPF8/L2083=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PRPF8+c.6247C%3ET
- 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= 0.00266953; MAF= 0.26695%, 4309/1614142 alleles, homozygotes = 89) and has highest observed frequency in the African/African American population (AF= 0.0489668; MAF= 4.89668%, 3673/75010 alleles, homozygotes = 86); grpmax FAF= 0.0476449.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.0046911; MAF= 0.46911%, 1327/282876 alleles, homozygotes = 32) and has highest observed frequency in the African/African American population (AF= 0.0480369; MAF= 4.80369%, 1199/24960 alleles, homozygotes = 31); grpmax FAF= 0.0458484.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0029862091432294497, 55/18418 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Benign (3 clinical laboratories). (ClinVarID = 321876)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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.