About PRPF8
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PRPF8 c.3299+14T>C, p.?
Classification
Not classified
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. Select a step to read what it means.
Not classified yet.Select a step to read what it means.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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Criteria may be applied incorrectly, sources may be misread, and a
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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: 4
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 4
BA1Stand alone
BA1 · stand alone
This variant has an allele frequency far exceeding the BA1 threshold of >1%. The grpmax filtering allele frequency is 4.48% in gnomAD v2.1 (African/African American subpopulation AF = 4.74%) and 4.65% in gnomAD v4.1 (African/African American subpopulation AF = 4.78%). Additionally, 34 homozygotes are observed in gnomAD v2.1 and 87 homozygotes in gnomAD v4.1, confirming this is a common polymorphism incompatible with a highly penetrant Mendelian disorder such as PRPF8-related retinitis pigmentosa.
BS1Strong
BS1 · strong
The overall allele frequency exceeds the BS1 threshold of >0.3%. gnomAD v2.1 overall AF = 0.455% (1286/282376 alleles). While gnomAD v4.1 overall AF = 0.251% is below the BS1 threshold, the v2.1 frequency meets the criterion. This criterion is effectively subsumed by BA1 (stand-alone benign) given the grpmax FAF of 4.5%, but is independently met based on population frequency.
BS2Strong
BS2 · strong
This variant has been observed in 34 homozygous individuals in gnomAD v2.1 and 87 homozygous individuals in gnomAD v4.1. PRPF8-related retinitis pigmentosa is inherited in an autosomal dominant manner. Observation of multiple healthy homozygous individuals for a dominant disorder is inconsistent with pathogenicity and satisfies BS2.
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence support a benign interpretation. SpliceAI predicts no splicing impact for this intronic variant (max delta score = 0.01), with no predicted acceptor gain, acceptor loss, donor gain, or donor loss. REVEL and BayesDel scores are not applicable to intronic variants. The SpliceAI prediction is specifically designed to detect splice-altering variants and finds no evidence of altered splicing at this position.
Recorded classification: Not classified
No source classification-combination explanation was recorded.
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
4,047 / 1,612,366 alleles
gnomAD v4.1: 4,047 / 1,612,366 alleles. Recorded AF 0.00250998. Recorded homozygote count 87.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00455421; MAF= 0.45542%, 1286/282376 alleles, homozygotes = 34) and has highest observed frequency in the African/African American population (AF= 0.0474283; MAF= 4.74283%, 1184/24964 alleles, homozygotes = 33); grpmax FAF= 0.044839.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0029335071707953064, 54/18408 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.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Statement recorded
In progress — evidence not uploaded yet.
No listed criterion applied
OncoKB ↗
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 4 met · 18 not met · 0 not assessed · 4 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.3299+14T>C is an intronic variant in PRPF8 located at position +14 of intron 21. The variant is present at extremely high frequency in population databases, with a grpmax filtering allele frequency of 4.48-4.65% in gnomAD and up to 4.78% in the African/African American subpopulation. This exceeds the BA1 stand-alone benign threshold of >1% by a wide margin.
The variant has been observed in 34 homozygous individuals in gnomAD v2.1 and 87 homozygous individuals in gnomAD v4.1, which is incompatible with autosomal dominant retinitis pigmentosa caused by PRPF8. This satisfies BS2 at strong benign strength.
SpliceAI predicts no splicing impact (max delta score = 0.01), with no predicted alterations to donor or acceptor sites, supporting a benign interpretation (BP4). No functional studies or clinical case reports were identified for this variant in the reviewed literature.
This variant has been classified as Benign by three clinical laboratories in ClinVar (VariationID 321893), though the review status is single-submitter and does not meet the 3-star expert panel threshold required for PP5/BP6 application under the governing framework.
Based on BA1 (stand-alone benign) alone, this variant is classified as Benign. BS1, BS2, and BP4 provide additional independent evidence supporting benign classification.
No criteria match.
Met · 4
BA1 Stand aloneThis variant has an allele frequency far exceeding the BA1 threshold of >1%. The grpmax filtering allele frequency is 4.48% in gnomAD v2.1 (African/African American subpopulation AF = 4.74%) and 4.65% in gnomAD v4.1 (African/African American subpopulation AF = 4.78%). Additionally, 34 homozygotes are observed in gnomAD v2.1 and 87 homozygotes in gnomAD v4.1, confirming this is a common polymorphism incompatible with a highly penetrant Mendelian disorder such as PRPF8-related retinitis pigmentosa. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 grpmax FAF = 4.48% (>> 1% BA1 threshold)
- gnomAD v4.1 grpmax FAF = 4.65% (>> 1% BA1 threshold)
- 34 homozygotes in v2.1
- 87 homozygotes in v4.1
- African/African American subpopulation AF = 4.74% in v2.1
- 4.78% in v4.1
Sources
BS1 StrongThe overall allele frequency exceeds the BS1 threshold of >0.3%. gnomAD v2.1 overall AF = 0.455% (1286/282376 alleles). While gnomAD v4.1 overall AF = 0.251% is below the BS1 threshold, the v2.1 frequency meets the criterion. This criterion is effectively subsumed by BA1 (stand-alone benign) given the grpmax FAF of 4.5%, but is independently met based on population frequency. Details ▾Hide ▴
BS2 StrongThis variant has been observed in 34 homozygous individuals in gnomAD v2.1 and 87 homozygous individuals in gnomAD v4.1. PRPF8-related retinitis pigmentosa is inherited in an autosomal dominant manner. Observation of multiple healthy homozygous individuals for a dominant disorder is inconsistent with pathogenicity and satisfies BS2. Details ▾Hide ▴
Evidence considered
- 34 homozygotes in gnomAD v2.1
- 87 homozygotes in gnomAD v4.1
- Inconsistent with autosomal dominant RP
Sources
BP4 SupportingMultiple lines of computational evidence support a benign interpretation. SpliceAI predicts no splicing impact for this intronic variant (max delta score = 0.01), with no predicted acceptor gain, acceptor loss, donor gain, or donor loss. REVEL and BayesDel scores are not applicable to intronic variants. The SpliceAI prediction is specifically designed to detect splice-altering variants and finds no evidence of altered splicing at this position. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01 (no predicted splicing impact)
- No donor/acceptor gain or loss predicted
Sources
Not met · 18 · evaluated, threshold not reached
PS2 No de novo observation was identified in any reviewed publication or case data for NM_006445.3:c.3299+14T>C. Details ▾Hide ▴
Evidence considered
- No de novo evidence found
Still missing
- No parental testing data available
PS3 No functional studies were identified for NM_006445.3:c.3299+14T>C. None of the reviewed publications contain variant-specific or systematically characterized range-based functional data for this intronic variant. SpliceAI predicts no splicing impact (max delta = 0.01), but this is in silico evidence (BP4), not experimental functional data satisfying PS3. Details ▾Hide ▴
Evidence considered
- No functional studies identified
- SpliceAI predicts no impact but is computational
- not experimental
Still missing
- No functional assays for this variant or surrounding region
Sources
PS4 No case-control studies or systematic cohort evidence was identified for this variant. The variant is too common in population databases (gnomAD v2.1 AF = 0.455% overall, 4.74% in African/African American) to be enriched in a rare disease cohort. None of the reviewed publications report patient-level observations of this variant. Details ▾Hide ▴
Evidence considered
- No case-control data
- Variant is common in population (AF up to 4.7%)
- No patient-level observations in reviewed literature
Sources
PM1 This is an intronic variant at position c.3299+14, not located in a characterized functional domain or mutational hotspot. The variant does not alter any protein coding sequence. No hotspot significance at cancerhotspots.org for this residue. Details ▾Hide ▴
Evidence considered
- Intronic variant outside functional domain
- No hotspot significance
PM2 This variant is present in gnomAD at frequencies far exceeding the PM2 threshold of <0.1%. gnomAD v2.1 overall AF = 0.455% (1286/282376 alleles, 34 homozygotes); gnomAD v4.1 overall AF = 0.251% (4047/1612366 alleles, 87 homozygotes). The variant is a common polymorphism. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 0.455%
- gnomAD v4.1 AF = 0.251%
- Both far exceed PM2 threshold of <0.1%
Sources
PM6 No de novo observation was identified in any reviewed publication or case data for NM_006445.3:c.3299+14T>C. None of the curated ClinVar submissions report de novo origin. Details ▾Hide ▴
Evidence considered
- No de novo evidence found
Still missing
- No parental testing data available
Sources
PP1 No segregation data was identified for this variant in any reviewed publication or case submission. Details ▾Hide ▴
Evidence considered
- No segregation analysis available
Still missing
- No family studies with this variant
PP2 This is an intronic variant, not a missense change. PP2 applies specifically to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. Not applicable to intronic substitutions. Details ▾Hide ▴
Evidence considered
- Intronic variant — not a missense change
PP3 No in silico evidence supports a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.01). REVEL and BayesDel scores are not available for intronic variants. No computational tool predicts pathogenicity for this variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01 (no impact)
- REVEL/BayesDel not applicable (intronic)
- HCI prior not supported for PRPF8
Sources
PP4 No specific patient phenotype data was provided for this case. No evidence that this variant was observed in an individual with a clinical presentation consistent with PRPF8-related disease (retinitis pigmentosa). Details ▾Hide ▴
Evidence considered
- No patient phenotype data available
Still missing
- No clinical phenotype information provided for proband
PP5 ClinVar classification is Benign, not Pathogenic/Likely Pathogenic. PP5 requires a reputable source (3-star expert panel) reporting the variant as pathogenic. This variant is classified as Benign by three clinical laboratories with review status 'criteria provided, single submitter' — not an expert panel review. Per the governing framework, PP5 is only applied at supporting strength with ClinVar 3-star EP classification; this entry does not qualify. Details ▾Hide ▴
Evidence considered
- ClinVar Benign (3 clinical labs)
- Review status: criteria provided
- single submitter
- No expert panel review — does not meet 3-star EP requirement for PP5
Sources
BS3 No functional studies were identified demonstrating that NM_006445.3:c.3299+14T>C has no deleterious effect. While SpliceAI predicts no splicing impact (delta = 0.01), this is in silico computational prediction (BP4), not experimental functional evidence. No in vitro or in vivo functional assays have tested this variant or a systematically characterized range that includes this position. Details ▾Hide ▴
Evidence considered
- No experimental functional data
- SpliceAI is computational
- not functional assay
Still missing
- No functional assays performed for this variant
Sources
BS4 No segregation data demonstrating lack of cosegregation with disease was identified for this variant. No family studies including this variant were found in the reviewed literature. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- No family studies with this variant
BP1 This is an intronic variant, not a missense change. BP1 applies specifically to missense variants in genes where primarily truncating variants cause disease. Additionally, PRPF8 is associated with disease through both missense and truncating pathogenic variants, so BP1 would not apply even for a missense variant. Details ▾Hide ▴
Evidence considered
- Intronic variant — not a missense change
- PRPF8 has both missense and truncating pathogenic variants
BP2 No evidence was identified of this variant being observed in trans with a known pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any reviewed publication or case submission. Details ▾Hide ▴
Evidence considered
- No phase information available
Still missing
- No cis/trans data with pathogenic variants
BP5 BP5 requires observation of the variant in a case with an alternate molecular basis for disease. No such case data was identified for this variant. Details ▾Hide ▴
Evidence considered
- No case with alternate molecular diagnosis identified
BP6 ClinVar classification is Benign with review status 'criteria provided, single submitter' — not a 3-star expert panel review. Per the governing framework, BP6 requires ClinVar 3-star expert panel classification to apply at supporting strength. The ClinVar entry for this variant (VariationID 321893) does not meet the expert panel threshold. Details ▾Hide ▴
Evidence considered
- ClinVar Benign (3 clinical labs)
- Review status: criteria provided
- single submitter
- No expert panel review — does not meet 3-star EP requirement for BP6
Sources
PS5 ClinVar classification is Benign, not Pathogenic. No reputable source reports this variant as pathogenic. The two criterion-lead submissions (SCV001733155, SCV005251965) both classify as Benign. Details ▾Hide ▴
Evidence considered
- ClinVar classification is Benign
- No reputable source reports as Pathogenic
Sources
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AIntronic variant at position c.3299+14 in intron 21, not affecting the canonical splice acceptor or donor sites (±1,2). Does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical splice consensus). SpliceAI predicts no splicing impact (max delta = 0.01). Details ▾Hide ▴
Evidence considered
- Intronic variant at +14 position
- SpliceAI max delta = 0.01
- Not in canonical splice consensus
Sources
spliceai ↗pvs1_variant_assessment
PS1 N/ANot applicable to intronic variants. PS1 requires a different nucleotide change at the same position with the same predicted amino acid effect, which cannot be evaluated for an intronic substitution. Details ▾Hide ▴
Evidence considered
- Intronic variant — no amino acid change
PM5 N/ANot applicable to intronic variants. PM5 requires a different missense change at the same residue with a pathogenic classification. This intronic variant has no amino acid residue context for comparator analysis. Details ▾Hide ▴
Evidence considered
- Intronic variant — no residue context
- No same-residue comparators available
Sources
pm5_candidates
BP7 N/ABP7 is specifically defined for synonymous (silent) coding variants with no predicted splicing impact and low nucleotide conservation. This is an intronic variant at position c.3299+14, not a synonymous coding change. BP7 does not apply to intronic substitutions. Details ▾Hide ▴
Evidence considered
- Intronic variant — not a synonymous coding change
Identifiers
- Gene
- PRPF8
- Transcript
- NM_006445.3
- Coding (HGVS c.)
- NM_006445.3:c.3299+14T>C
- Protein (HGVS p.)
- NP_006436.3:p.?
- GRCh38
- chr17:1674428 A>G
- GRCh37
- chr17:1577722 A>G
- ClinVar
- 321893
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
4,047 / 1,612,366 alleles
AF 0.00251 · 87 homozygotes · FAF 0.0465
gnomAD v2.1
1,286 / 282,376 alleles
AF 0.00455 · 34 homozygotes · FAF 0.0448
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 0.0025 · 4047 / 1,612,366 alleles · 87 hom · FAF 0.046
| African/African American3584 / 74,986 | 0.04885 hom |
| Remaining individuals182 / 62,430 | 0.00291 hom |
| Admixed American171 / 60,014 | 0.0028 |
| Middle Eastern17 / 6,038 | 0.0028 |
| South Asian20 / 91,026 | 0.000221 hom |
| European (non-Finnish)73 / 1,178,438 | 6.2e-05 |
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, East Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.0046 · 1286 / 282,376 alleles · 34 hom · FAF 0.045
| African/African American1184 / 24,964 | 0.04733 hom |
| Admixed American75 / 35,438 | 0.0021 |
| Remaining individuals11 / 7,220 | 0.0015 |
| South Asian8 / 30,616 | 0.000261 hom |
| European (non-Finnish)8 / 128,702 | 6.2e-05 |
0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, East Asian, European (Finnish).
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00250998; MAF= 0.25100%, 4047/1612366 alleles, homozygotes = 87) and has highest observed frequency in the African/African American population (AF= 0.0477956; MAF= 4.77956%, 3584/74986 alleles, homozygotes = 85); grpmax FAF= 0.0464895.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00455421; MAF= 0.45542%, 1286/282376 alleles, homozygotes = 34) and has highest observed frequency in the African/African American population (AF= 0.0474283; MAF= 4.74283%, 1184/24964 alleles, homozygotes = 33); grpmax FAF= 0.044839.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0029335071707953064, 54/18408 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 support a benign interpretation. SpliceAI predicts no splicing impact for this intronic variant (max delta score = 0.01), with no predicted acceptor gain, acceptor loss, donor gain, or donor loss. REVEL and BayesDel scores are not applicable to intronic variants. The SpliceAI prediction is specifically designed to detect splice-altering variants and finds no evidence of altered splicing at this position. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01 (no predicted splicing impact)
- No donor/acceptor gain or loss predicted
Sources
PP3 No in silico evidence supports a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.01). REVEL and BayesDel scores are not available for intronic variants. No computational tool predicts pathogenicity for this variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01 (no impact)
- REVEL/BayesDel not applicable (intronic)
- HCI prior not supported for PRPF8
Sources
BP7 N/ABP7 is specifically defined for synonymous (silent) coding variants with no predicted splicing impact and low nucleotide conservation. This is an intronic variant at position c.3299+14, not a synonymous coding change. BP7 does not apply to intronic substitutions. Details ▾Hide ▴
Evidence considered
- Intronic variant — not a synonymous coding change
Statement
In silico
In progress — evidence not uploaded yet.
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.No 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).No 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
4,047 / 1,612,366 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 ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/321893/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-1577722-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-1674428-A-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-1674428-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006445.3%3Ac.3299…
- OncoKB ↗www.oncokb.org/gene/PRPF8/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PRPF8+c.3299+14T%3EC
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= 0.00250998; MAF= 0.25100%, 4047/1612366 alleles, homozygotes = 87) and has highest observed frequency in the African/African American population (AF= 0.0477956; MAF= 4.77956%, 3584/74986 alleles, homozygotes = 85); grpmax FAF= 0.0464895.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00455421; MAF= 0.45542%, 1286/282376 alleles, homozygotes = 34) and has highest observed frequency in the African/African American population (AF= 0.0474283; MAF= 4.74283%, 1184/24964 alleles, homozygotes = 33); grpmax FAF= 0.044839.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0029335071707953064, 54/18408 alleles, homozygotes = 0).
ClinVar
In progress — evidence not uploaded yet.
In silico
In progress — evidence not uploaded yet.
Functional
In progress — evidence not uploaded yet.
Somatic
In progress — evidence not uploaded yet.
Literature
In progress — evidence not uploaded yet.