About PRPF8
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PRPF8 c.1929C>T, p.(Gly643=)
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
BS1Supporting
BS1 · supporting
The grpmax filtering allele frequency exceeds the 0.3% threshold for BS1 (0.524% in gnomAD v2.1; 0.629% in gnomAD v4.1), and 3 homozygotes are observed in v4.1, indicating this variant is more common than expected for a fully penetrant dominant disorder.
BS2Supporting
BS2 · supporting
Three homozygous individuals for this variant are observed in gnomAD v4.1 (total 568 alleles, 3 homozygotes). For a gene associated with autosomal dominant retinitis pigmentosa, the presence of homozygous individuals in a population database is inconsistent with a highly penetrant pathogenic variant.
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on gene product. SpliceAI predicts no significant splice alteration (max delta 0.10, below the 0.2 threshold), and the variant is synonymous with no amino acid change. REVEL and BayesDel are not applicable.
BP7Supporting
BP7 · supporting
This is a synonymous variant (p.Gly643=) at a nucleotide position that is not highly conserved, with SpliceAI predicting no significant splice impact (max delta 0.10). The high population frequency in the African population (AF 0.62–0.68%) with 3 homozygotes in gnomAD v4.1 further supports that this nucleotide position tolerates variation.
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
568 / 1,613,942 alleles
gnomAD v4.1: 568 / 1,613,942 alleles. Recorded AF 0.000351933. Recorded homozygote count 3.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000590653; MAF= 0.05907%, 167/282738 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.0061773; MAF= 0.61773%, 154/24930 alleles, homozygotes = 0); grpmax FAF= 0.00523856.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027150304083405736, 5/18416 alleles, homozygotes = 0).
SpliceAI score
0.100 maximum delta
Recorded SpliceAI maximum delta score: 0.100. 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
In progress — evidence not uploaded yet.
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: 4 met · 16 not met · 0 not assessed · 6 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.1929C>T (p.Gly643=) is a synonymous variant in PRPF8 with no predicted splice impact (SpliceAI max delta 0.10).
This variant is present in gnomAD v2.1 at an overall allele frequency of 0.059% (167/282,738 alleles) with a grpmax filtering allele frequency of 0.524% in the African/African American population, exceeding the 0.3% threshold for BS1.
In gnomAD v4.1, the variant is observed at an overall frequency of 0.035% (568/1,613,942 alleles) with a grpmax FAF of 0.629% and 3 homozygous individuals, confirming it is established in the general population at frequencies inconsistent with a fully penetrant pathogenic variant.
ClinVar classifies this variant as Benign (2 clinical laboratories) and Likely benign (1 clinical laboratory), with a 2-star review status (criteria provided, multiple submitters, no conflicts). Three independent clinical laboratories have reached a benign or likely benign conclusion.
Based on the generic ACMG/AMP 2015 framework, the variant meets BS1 (supporting benign), BS2 (supporting benign), BP4 (supporting benign), and BP7 (supporting benign), totaling 4 supporting benign criteria, consistent with a classification of Likely Benign.
No criteria match.
Met · 4
BS1 SupportingThe grpmax filtering allele frequency exceeds the 0.3% threshold for BS1 (0.524% in gnomAD v2.1; 0.629% in gnomAD v4.1), and 3 homozygotes are observed in v4.1, indicating this variant is more common than expected for a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: grpmax FAF 0.524% (AFR)
- gnomAD v4.1: grpmax FAF 0.629% (AFR)
- 3 homozygotes.
Sources
BS2 SupportingThree homozygous individuals for this variant are observed in gnomAD v4.1 (total 568 alleles, 3 homozygotes). For a gene associated with autosomal dominant retinitis pigmentosa, the presence of homozygous individuals in a population database is inconsistent with a highly penetrant pathogenic variant. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 3 homozygous individuals observed
- consistent with benign variation.
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product. SpliceAI predicts no significant splice alteration (max delta 0.10, below the 0.2 threshold), and the variant is synonymous with no amino acid change. REVEL and BayesDel are not applicable. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.10 (no predicted splice impact)
- synonymous variant with no amino acid alteration.
Sources
BP7 SupportingThis is a synonymous variant (p.Gly643=) at a nucleotide position that is not highly conserved, with SpliceAI predicting no significant splice impact (max delta 0.10). The high population frequency in the African population (AF 0.62–0.68%) with 3 homozygotes in gnomAD v4.1 further supports that this nucleotide position tolerates variation. Details ▾Hide ▴
Evidence considered
- Synonymous variant (p.Gly643=)
- SpliceAI max delta 0.10 confirming no cryptic splice site creation
- high population frequency indicates nucleotide not under strong selective constraint.
Sources
Not met · 16 · evaluated, threshold not reached
PS2 No de novo confirmation data are available for this variant. Details ▾Hide ▴
Still missing
- No de novo testing or trio data available.
PS3 No variant-specific functional data were identified for NM_006445.3:c.1929C>T. The literature reviewed contains no experimental characterization of this synonymous variant. Details ▾Hide ▴
Still missing
- No functional studies of this variant available in the literature.
PS4 No case-control or prevalence data are available comparing affected versus unaffected individuals for this variant. Details ▾Hide ▴
Still missing
- No patient cohort or case-control data available.
PM1 No statistically significant hotspot was identified at this residue in cancerhotspots.org, and while PRPF8 encodes a core spliceosome component, there is no evidence that this synonymous position falls within a critical functional domain where synonymous changes are known to be pathogenic. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: no significant hotspot at residue 643. The variant is synonymous and is not located in a known critical functional domain for synonymous alterations.
PM2 While the overall gnomAD allele frequency (0.059% v2.1, 0.035% v4.1) is below the 0.1% PM2 threshold, the grpmax filtering allele frequency is elevated (0.524% v2.1, 0.629% v4.1) with 3 homozygotes observed in v4.1, indicating this variant is well-established in certain populations and does not meet the intent of PM2 as a rare variant criterion. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 167/282
- 738 alleles (AF 0.059%)
- grpmax FAF 0.524% in AFR
- gnomAD v4.1: 568/1
- 613
- 942 alleles (AF 0.035%)
- 3 homozygotes
- grpmax FAF 0.629% in AFR.
Sources
PM6 No de novo observation has been reported for this variant. Details ▾Hide ▴
Still missing
- No de novo data available.
PP1 No co-segregation data are available for this variant. Details ▾Hide ▴
Still missing
- No family segregation data available.
PP3 Multiple computational predictors do not support a deleterious effect. SpliceAI predicts no significant splice impact (max delta 0.10), and REVEL/BayesDel scores are not available for this synonymous variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.10 (below 0.2 threshold for splice effect)
- REVEL and BayesDel not applicable for synonymous variant.
Sources
PP4 No proband phenotype or family history data are available for evaluation. Details ▾Hide ▴
Still missing
- No patient phenotype data available.
PP5 ClinVar reports this variant as Benign/Likely benign (2-star, criteria provided, multiple submitters, no conflicts). PP5 requires a reputable source reporting the variant as pathogenic; this does not apply. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 281811: Benign (2 clinical labs)
- Likely benign (1 clinical lab)
- no submissions classify as pathogenic.
Sources
BA1 The overall gnomAD allele frequency (0.059% v2.1, 0.035% v4.1) and grpmax filtering allele frequency (0.524% v2.1, 0.629% v4.1) are both below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF 0.059%
- grpmax FAF 0.524%
- gnomAD v4.1 AF 0.035%
- grpmax FAF 0.629%. Neither exceeds the 1% BA1 threshold.
Sources
BS3 No in vitro or in vivo functional studies demonstrating a benign effect were identified for this variant. Details ▾Hide ▴
Still missing
- No functional studies available.
BS4 No family segregation data demonstrating lack of co-segregation with disease are available. Details ▾Hide ▴
Still missing
- No segregation data available.
BP2 No observation of this variant in trans with a known pathogenic variant has been reported. Details ▾Hide ▴
Still missing
- No trans-phase data available.
BP5 No evidence that an alternative molecular basis for disease has been identified in a case carrying this variant. Details ▾Hide ▴
Still missing
- No alternative molecular cause data available.
BP6 ClinVar reports this variant as Benign/Likely benign with a 2-star review status (criteria provided, multiple submitters, no conflicts), but this does not meet the 3-star expert panel threshold required for BP6 application under the generic ACMG framework. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 281811: Benign/Likely benign
- 2-star
- 3 clinical laboratory submissions without expert panel review.
Sources
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_006445.3:c.1929C>T is a synonymous variant (p.Gly643=) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Details ▾Hide ▴
Evidence considered
- Synonymous variant with no predicted protein truncation or splice disruption
- PVS1 not applicable per ClinGen SVI PVS1 recommendations (PMC6185798).
Sources
pvs1_generic_framework
PS1 N/APS1 applies to variants producing the same amino acid change as an established pathogenic variant. This synonymous variant produces no amino acid change. Details ▾Hide ▴
Evidence considered
- Synonymous variant (p.Gly643=)
- no amino acid change to compare to known pathogenic variants.
PM5 N/APM5 requires a different pathogenic missense change at the same residue. This variant is synonymous (p.Gly643=) and cannot be assessed for same-residue missense comparator semantics. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- no residue change to compare.
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. This is a synonymous variant. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- PP2 is specific to missense variants.
BP1 N/ABP1 applies to missense variants in genes where truncating variants are a known disease mechanism. This is a synonymous variant. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- BP1 is specific to missense variants.
PS5 N/APS5 is not a standard generic ACMG/AMP 2015 criterion. No gene-specific VCEP defines PS5 for PRPF8. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- PRPF8
- Transcript
- NM_006445.3
- Coding (HGVS c.)
- NM_006445.3:c.1929C>T
- Protein (HGVS p.)
- NP_006436.3:p.(Gly643=)
- GRCh38
- chr17:1677620 G>A
- GRCh37
- chr17:1580914 G>A
- ClinVar
- 281811
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
568 / 1,613,942 alleles
AF 0.000352 · 3 homozygotes · FAF 0.00629
gnomAD v2.1
167 / 282,738 alleles
AF 0.000591 · 0 homozygotes · FAF 0.00524
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 0.00035 · 568 / 1,613,942 alleles · 3 hom · FAF 0.0063
| African/African American508 / 74,950 | 0.00683 hom |
| Middle Eastern4 / 6,060 | 0.00066 |
| Remaining individuals30 / 62,506 | 0.00048 |
| Admixed American23 / 59,982 | 0.00038 |
| South Asian2 / 91,076 | 2.2e-05 |
| European (non-Finnish)1 / 1,180,000 | 8.5e-07 |
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, East Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00059 · 167 / 282,738 alleles · 0 hom · FAF 0.0052
| African/African American154 / 24,930 | 0.0062 |
| Admixed American11 / 35,432 | 0.00031 |
| Remaining individuals2 / 7,224 | 0.00028 |
0 alternate alleles recorded in 5 other groups: Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), South Asian.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000351933; MAF= 0.03519%, 568/1613942 alleles, homozygotes = 3) and has highest observed frequency in the African/African American population (AF= 0.00677785; MAF= 0.67779%, 508/74950 alleles, homozygotes = 3); grpmax FAF= 0.0062901.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000590653; MAF= 0.05907%, 167/282738 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.0061773; MAF= 0.61773%, 154/24930 alleles, homozygotes = 0); grpmax FAF= 0.00523856.
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 gene product. SpliceAI predicts no significant splice alteration (max delta 0.10, below the 0.2 threshold), and the variant is synonymous with no amino acid change. REVEL and BayesDel are not applicable. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.10 (no predicted splice impact)
- synonymous variant with no amino acid alteration.
Sources
BP7 SupportingThis is a synonymous variant (p.Gly643=) at a nucleotide position that is not highly conserved, with SpliceAI predicting no significant splice impact (max delta 0.10). The high population frequency in the African population (AF 0.62–0.68%) with 3 homozygotes in gnomAD v4.1 further supports that this nucleotide position tolerates variation. Details ▾Hide ▴
Evidence considered
- Synonymous variant (p.Gly643=)
- SpliceAI max delta 0.10 confirming no cryptic splice site creation
- high population frequency indicates nucleotide not under strong selective constraint.
Sources
PP3 Multiple computational predictors do not support a deleterious effect. SpliceAI predicts no significant splice impact (max delta 0.10), and REVEL/BayesDel scores are not available for this synonymous variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.10 (below 0.2 threshold for splice effect)
- REVEL and BayesDel not applicable for synonymous variant.
Sources
Statement
In silico
In progress — evidence not uploaded yet.
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. · 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
568 / 1,613,942 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.100
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/281811/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-1580914-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-1677620-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-1677620-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006445.3%3Ac.1929…
- OncoKB ↗www.oncokb.org/gene/PRPF8/G643=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PRPF8+c.1929C%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= 0.000351933; MAF= 0.03519%, 568/1613942 alleles, homozygotes = 3) and has highest observed frequency in the African/African American population (AF= 0.00677785; MAF= 0.67779%, 508/74950 alleles, homozygotes = 3); grpmax FAF= 0.0062901.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000590653; MAF= 0.05907%, 167/282738 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.0061773; MAF= 0.61773%, 154/24930 alleles, homozygotes = 0); grpmax FAF= 0.00523856.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027150304083405736, 5/18416 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.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Literature
In progress — evidence not uploaded yet.