About PRPF8
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PRPF8 c.1666C>T, p.(Leu556=)
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
The allele frequency of this variant is greater than expected for a PRPF8-associated disorder (retinitis pigmentosa). gnomAD v4.1 grpmax filtering allele frequency is 0.632%, exceeding the BS1 threshold of >0.3%. In the African/African American population, the allele frequency is 0.681% (511/75,040 alleles) with 3 homozygotes, confirming this variant is too common to cause a highly penetrant dominant disease.
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splice alteration (max delta score = 0.00). As a synonymous variant without predicted splicing effects, the nucleotide substitution is not expected to alter protein sequence or function.
BP7Supporting
BP7 · supporting
NM_006445.3:c.1666C>T is a synonymous variant (p.Leu556=) for which SpliceAI predicts no impact on splicing (max delta score = 0.00). The nucleotide is observed at appreciable frequency in population databases (gnomAD v4.1: 3 homozygotes, African/African American AF = 0.681%), consistent with a lack of strong evolutionary constraint at this position.
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, BP4 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
572 / 1,614,118 alleles
gnomAD v4.1: 572 / 1,614,118 alleles. Recorded AF 0.000354373. Recorded homozygote count 3.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00058816; MAF= 0.05882%, 166/282236 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00614162; MAF= 0.61416%, 153/24912 alleles, homozygotes = 0); grpmax FAF= 0.00524827.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027150304083405736, 5/18416 alleles, homozygotes = 0).
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
3 reported laboratory submissions
2 Benign · 1 Likely benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
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.
26 criteria with recorded statuses: 3 met · 15 not met · 0 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_006445.3:c.1666C>T (p.Leu556=) is a synonymous variant in PRPF8, a gene associated with autosomal dominant retinitis pigmentosa.
This variant is present in population databases at frequencies too high for a highly penetrant pathogenic variant: gnomAD v4.1 grpmax filtering allele frequency is 0.632%, with 3 homozygotes observed in the African/African American population (AF = 0.681%).
SpliceAI predicts no impact on splicing (max delta score = 0.00), consistent with a synonymous variant that does not alter the gene product or create/disrupt splice sites.
ClinVar reports this variant as Benign (2 clinical laboratories) or Likely benign (1 clinical laboratory), though review status is single-submitter level (1-star).
This variant meets BS1 (strong benign, allele frequency >0.3%), BP4 (supporting benign, no predicted splice impact), and BP7 (supporting benign, synonymous variant with no splice effect). No pathogenic criteria are met.
No criteria match.
Met · 3
BS1 StrongThe allele frequency of this variant is greater than expected for a PRPF8-associated disorder (retinitis pigmentosa). gnomAD v4.1 grpmax filtering allele frequency is 0.632%, exceeding the BS1 threshold of >0.3%. In the African/African American population, the allele frequency is 0.681% (511/75,040 alleles) with 3 homozygotes, confirming this variant is too common to cause a highly penetrant dominant disease. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: grpmax FAF 0.632% (>0.3% BS1 threshold)
- African/African American AF 0.681% with 3 homozygotes.
- gnomAD v2.1: grpmax FAF 0.525% (>0.3% BS1 threshold)
- African/African American AF 0.614%.
- PRPF8-associated retinitis pigmentosa is a rare dominant disorder
- an allele frequency of >0.6% in any population is incompatible with high-penetrance pathogenicity.
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splice alteration (max delta score = 0.00). As a synonymous variant without predicted splicing effects, the nucleotide substitution is not expected to alter protein sequence or function. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 across all categories (acceptor gain
- acceptor loss
- donor gain
- donor loss all null).
- Synonymous variant with no predicted effect on splicing or protein sequence.
Sources
BP7 SupportingNM_006445.3:c.1666C>T is a synonymous variant (p.Leu556=) for which SpliceAI predicts no impact on splicing (max delta score = 0.00). The nucleotide is observed at appreciable frequency in population databases (gnomAD v4.1: 3 homozygotes, African/African American AF = 0.681%), consistent with a lack of strong evolutionary constraint at this position. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- no predicted creation or disruption of splice sites.
- gnomAD v4.1: 3 homozygotes
- AF 0.681% in African/African American population
- indicating the nucleotide position is not under strong purifying selection.
Sources
Not met · 15 · evaluated, threshold not reached
PS3 No functional data identified for NM_006445.3:c.1666C>T. SpliceAI predicts no splice impact (max delta score = 0.00). No in vitro or in vivo functional studies of this variant were identified in the literature. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- no REVEL or BayesDel scores available
- no publications with variant-specific functional data.
Still missing
- No functional characterization of this synonymous variant.
Sources
PS4 No case-specific prevalence data available. The variant is observed in population databases at frequencies inconsistent with a highly penetrant pathogenic variant (3 homozygotes in gnomAD v4.1). Details ▾Hide ▴
Evidence considered
- ClinVar submissions from clinical testing laboratories do not provide patient phenotype or case counts specific to this variant.
- gnomAD v4.1: 3 homozygotes
- grpmax FAF 0.632%.
Still missing
- No case-control or cohort data for this variant.
Sources
PM1 This synonymous variant is not located in a statistically significant mutational hotspot (cancerhotspots.org negative). SpliceAI predicts no splice disruption (max delta = 0.00). No evidence that this synonymous change disrupts a critical functional domain. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue not significant
- exact variant not listed.
- SpliceAI max delta = 0.00.
Sources
PM2 Present in gnomAD at frequencies exceeding the PM2 threshold of <0.1%. gnomAD v4.1 grpmax filtering allele frequency is 0.632% (511/75,040 alleles in African/African American population with 3 homozygotes). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF 0.0588% (166/282
- 236)
- grpmax FAF 0.525%
- gnomAD v4.1: AF 0.0354% (572/1
- 614
- 118)
- grpmax FAF 0.632%
- 3 homozygotes total
- Highest subpopulation: African/African American AF 0.681% (511/75
- 040
- 3 homozygotes)
Sources
PP1 No cosegregation data available for this variant. Details ▾Hide ▴
Evidence considered
- No family segregation studies identified.
Still missing
- No family studies with segregation analysis.
PP3 No computational evidence supports a deleterious effect. SpliceAI predicts no splice impact (max delta = 0.00). REVEL and BayesDel scores are not available for this variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- no REVEL score available
- no BayesDel score available.
Still missing
- REVEL and BayesDel not computed for this genomic position.
Sources
PP4 No patient phenotype data available to assess specificity to PRPF8-associated disease (retinitis pigmentosa). Details ▾Hide ▴
Evidence considered
- ClinVar submissions lack detailed patient phenotype data.
Still missing
- No phenotype information for individuals carrying this variant.
PP5 ClinVar classification for this variant is Benign, not Pathogenic. PP5 requires a pathogenic assertion from a reputable source. Details ▾Hide ▴
Evidence considered
- ClinVar: Benign (2 clinical laboratories)
- Likely benign (1 clinical laboratory)
- review status: criteria provided
- single submitter (1-star).
Sources
BA1 Maximum population allele frequency (gnomAD v4.1 grpmax FAF = 0.632%) is below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 0.632%
- gnomAD v2.1 grpmax FAF = 0.525%.
Sources
BS2 No confirmed clinical observation of this variant in a healthy adult individual for a fully penetrant dominant disorder expected at an early age. However, the presence of 3 homozygotes in gnomAD v4.1 strongly suggests this variant is tolerated in the homozygous state in population databases screened for severe pediatric disease. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 3 homozygotes in the African/African American population
- suggesting tolerance in the homozygous state.
- No confirmed phenotype data for homozygous individuals.
Still missing
- No confirmed healthy adult observation with phenotype data for BS2 criteria.
Sources
BS3 No functional studies demonstrating a benign effect for NM_006445.3:c.1666C>T were identified. SpliceAI predicts no splice impact (max delta = 0.00), but in silico predictions alone are insufficient to meet BS3. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- no in vitro or in vivo functional studies demonstrating normal function.
Still missing
- No functional characterization studies for this variant.
Sources
BS4 No segregation data available. BS4 requires a lack of cosegregation in affected family members. Details ▾Hide ▴
Evidence considered
- No family segregation studies identified.
Still missing
- No family studies available.
BP2 No data on observation of this variant in trans with a known pathogenic PRPF8 variant. Details ▾Hide ▴
Evidence considered
- No phase information available.
Still missing
- No data on in trans observations with pathogenic variants.
BP5 No data indicating an alternate molecular basis for disease in an individual carrying this variant. Details ▾Hide ▴
Evidence considered
- No cases identified with an alternate molecular cause.
Still missing
- No reports of this variant found in cases with a confirmed alternate genetic etiology.
BP6 ClinVar classifies this variant as Benign, but the review status is only 'criteria provided, single submitter' (1-star). BP6 requires a reputable source with strong evidence, typically an expert panel (3-star) review. The available ClinVar assertion does not reach the threshold for BP6 application. Details ▾Hide ▴
Evidence considered
- ClinVar: Benign/Likely benign (3 submitters
- all single submitter
- no expert panel).
- Review status: 'criteria provided
- single submitter' (1-star)
- PP5/BP6 supporting-level application requires 3-star expert panel review.
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ASynonymous variant (NP_006436.3:p.(Leu556=)) does not alter the protein sequence; PVS1 requires a predicted null variant mechanism (nonsense, frameshift, canonical splice, initiation codon, or exon deletion). Details ▾Hide ▴
Evidence considered
- Synonymous substitution c.1666C>T produces no amino acid change
- variant does not fall into any PVS1 null-variant bucket per ClinGen SVI PVS1 recommendations (PMC6185798).
Sources
pvs1_variant_assessment
PS1 N/ASynonymous variant produces no amino acid change; PS1 requires a variant with the same amino acid change as an established pathogenic missense variant. Details ▾Hide ▴
Evidence considered
- Variant is synonymous (p.Leu556=)
- no amino acid alteration.
PS2 N/ANo de novo data available for NM_006445.3:c.1666C>T. Details ▾Hide ▴
Evidence considered
- No de novo observations identified in ClinVar submissions or the literature reviewed.
Still missing
- No trio or de novo testing data available.
PM5 N/ASynonymous variant with no amino acid change; PM5 requires a different missense alteration at the same amino acid residue compared to an established pathogenic missense variant. PM5 candidate harvesting was unable to parse a missense residue context. Details ▾Hide ▴
Evidence considered
- Protein consequence NP_006436.3:p.(Leu556=) is synonymous
- no residue-level candidates identifiable.
Sources
pm5_candidates
PM6 N/ANo de novo data available for this variant; no trio or parentage-confirmed de novo observations were identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No de novo reports for NM_006445.3:c.1666C>T identified.
Still missing
- No de novo testing data available.
PP2 N/ASynonymous variant; PP2 is specific to missense variants in genes with a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
- Variant is synonymous (p.Leu556=)
- not missense.
BP1 N/ASynonymous variant; BP1 is specific to missense variants in genes where primarily truncating variants are known to cause disease. Details ▾Hide ▴
Evidence considered
- Variant is synonymous (p.Leu556=)
- not missense.
PS5 N/ASynonymous variant produces no amino acid change; PS5 requires a novel missense change at an amino acid residue where a different pathogenic missense change has been established. Details ▾Hide ▴
Evidence considered
- Variant is synonymous (p.Leu556=)
- no residue alteration.
Identifiers
- Gene
- PRPF8
- Transcript
- NM_006445.3
- Coding (HGVS c.)
- NM_006445.3:c.1666C>T
- Protein (HGVS p.)
- NP_006436.3:p.(Leu556=)
- GRCh38
- chr17:1678815 G>A
- GRCh37
- chr17:1582109 G>A
- ClinVar
- 281806
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
572 / 1,614,118 alleles
AF 0.000354 · 3 homozygotes · FAF 0.00632
gnomAD v2.1
166 / 282,236 alleles
AF 0.000588 · 0 homozygotes · FAF 0.00525
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00035 · 572 / 1,614,118 alleles · 3 hom · FAF 0.0063
| African/African American511 / 75,040 | 0.00683 hom |
| Middle Eastern4 / 6,062 | 0.00066 |
| Remaining individuals30 / 62,508 | 0.00048 |
| Admixed American23 / 60,018 | 0.00038 |
| South Asian3 / 91,082 | 3.3e-05 |
| European (non-Finnish)1 / 1,180,028 | 8.5e-07 |
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, East Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00059 · 166 / 282,236 alleles · 0 hom · FAF 0.0052
| African/African American153 / 24,912 | 0.0061 |
| Admixed American11 / 35,426 | 0.00031 |
| Remaining individuals2 / 7,212 | 0.00028 |
0 alternate alleles recorded in 5 other groups: Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), South Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000354373; MAF= 0.03544%, 572/1614118 alleles, homozygotes = 3) and has highest observed frequency in the African/African American population (AF= 0.0068097; MAF= 0.68097%, 511/75040 alleles, homozygotes = 3); grpmax FAF= 0.00632119.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00058816; MAF= 0.05882%, 166/282236 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00614162; MAF= 0.61416%, 153/24912 alleles, homozygotes = 0); grpmax FAF= 0.00524827.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027150304083405736, 5/18416 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splice alteration (max delta score = 0.00). As a synonymous variant without predicted splicing effects, the nucleotide substitution is not expected to alter protein sequence or function. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 across all categories (acceptor gain
- acceptor loss
- donor gain
- donor loss all null).
- Synonymous variant with no predicted effect on splicing or protein sequence.
Sources
BP7 SupportingNM_006445.3:c.1666C>T is a synonymous variant (p.Leu556=) for which SpliceAI predicts no impact on splicing (max delta score = 0.00). The nucleotide is observed at appreciable frequency in population databases (gnomAD v4.1: 3 homozygotes, African/African American AF = 0.681%), consistent with a lack of strong evolutionary constraint at this position. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- no predicted creation or disruption of splice sites.
- gnomAD v4.1: 3 homozygotes
- AF 0.681% in African/African American population
- indicating the nucleotide position is not under strong purifying selection.
Sources
PP3 No computational evidence supports a deleterious effect. SpliceAI predicts no splice impact (max delta = 0.00). REVEL and BayesDel scores are not available for this variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- no REVEL score available
- no BayesDel score available.
Still missing
- REVEL and BayesDel not computed for this genomic position.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
1 paper record 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
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Describes the Sherloc variant classification framework, a refinement of ACMG-AMP criteria. NM_006445.3:c.1666C>T (PRPF8 p.Leu556=) was not identified in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
572 / 1,614,118 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
2 Benign · 1 Likely 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/281806/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-1582109-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-1678815-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-1678815-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006445.3%3Ac.1666…
- OncoKB ↗www.oncokb.org/gene/PRPF8/L556=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PRPF8+c.1666C%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= 0.000354373; MAF= 0.03544%, 572/1614118 alleles, homozygotes = 3) and has highest observed frequency in the African/African American population (AF= 0.0068097; MAF= 0.68097%, 511/75040 alleles, homozygotes = 3); grpmax FAF= 0.00632119.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00058816; MAF= 0.05882%, 166/282236 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00614162; MAF= 0.61416%, 153/24912 alleles, homozygotes = 0); grpmax FAF= 0.00524827.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027150304083405736, 5/18416 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Benign (2 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 281806)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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.