About PRPF8
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PRPF8 c.471T>C, p.(Asp157=)
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.
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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: 1
Benign evidence criteria: 3
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is present in gnomAD at extremely low allele frequency: 6/282,676 alleles (AF=0.00212%) in v2.1 and 17/1,613,606 alleles (AF=0.00105%) in v4.1, both well below the non-VCEP threshold of 0.1%. No homozygotes observed.
Benign criteria applied · 3
BP4Supporting
BP4 · supporting
SpliceAI predicts no splicing impact for this synonymous variant (max delta score = 0.00). Multiple lines of computational evidence suggest no effect on the gene product.
BP6Supporting
BP6 · supporting
This variant has been reported in ClinVar as Likely benign by Labcorp Genetics (formerly Invitae), a reputable clinical diagnostic laboratory, with criteria provided (SCV001672660).
BP7Supporting
BP7 · supporting
This is a synonymous variant (p.Asp157=) with SpliceAI delta score of 0.00, indicating no predicted impact on splicing. The nucleotide substitution is not predicted to affect mRNA processing.
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: PM2 supporting, BP4 supporting benign, BP6 supporting benign, BP7 supporting benign; combination = 1 supporting + 3 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
17 / 1,613,606 alleles
gnomAD v4.1: 17 / 1,613,606 alleles. Recorded AF 1.05354e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.12257e-05; MAF= 0.00212%, 6/282676 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 8.46597e-05; MAF= 0.00847%, 3/35436 alleles, homozygotes = 0); grpmax FAF= 4.09e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Likely benign.
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: 4 met · 5 not met · 12 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.471T>C is a synonymous variant (p.Asp157=) in PRPF8 that is present at extremely low frequency in population databases (gnomAD v2.1: 6/282,676 alleles, AF=0.00212%; gnomAD v4.1: 17/1,613,606 alleles, AF=0.00105%).
SpliceAI predicts no splicing impact for this variant (max delta score = 0.00), consistent with a synonymous change that does not alter the protein sequence or mRNA processing.
This variant has been reported in ClinVar as Likely benign by Labcorp Genetics (formerly Invitae), a reputable clinical laboratory, with criteria provided (ClinVar Variation ID: 1133865, SCV001672660).
No published literature identifies NM_006445.3:c.471T>C in association with disease; the sole ClinVar-cited reference (PMID:28492532, Sherloc framework paper) does not mention this specific variant.
Three supporting benign criteria (BP4, BP6, BP7) outweigh one supporting pathogenic criterion (PM2). Under ACMG/AMP 2015 combination rules (PMID:25741868), this yields a final classification of Likely benign.
No criteria match.
Met · 4
PM2 SupportingThis variant is present in gnomAD at extremely low allele frequency: 6/282,676 alleles (AF=0.00212%) in v2.1 and 17/1,613,606 alleles (AF=0.00105%) in v4.1, both well below the non-VCEP threshold of 0.1%. No homozygotes observed. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 6/282676 alleles (AF=0.00212%)
- gnomAD v4.1: 17/1613606 alleles (AF=0.00105%)
- no homozygotes.
Sources
BP4 SupportingSpliceAI predicts no splicing impact for this synonymous variant (max delta score = 0.00). Multiple lines of computational evidence suggest no effect on the gene product. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- no predicted effect on splicing
- synonymous variant with no amino acid change.
Sources
BP6 SupportingThis variant has been reported in ClinVar as Likely benign by Labcorp Genetics (formerly Invitae), a reputable clinical diagnostic laboratory, with criteria provided (SCV001672660). Details ▾Hide ▴
Evidence considered
- ClinVar: Likely benign
- criteria provided
- single submitter (Labcorp/Invitae
- SCV001672660).
Sources
BP7 SupportingThis is a synonymous variant (p.Asp157=) with SpliceAI delta score of 0.00, indicating no predicted impact on splicing. The nucleotide substitution is not predicted to affect mRNA processing. Details ▾Hide ▴
Evidence considered
- Synonymous variant at c.471T>C (p.Asp157=)
- SpliceAI max delta = 0.00
- no predicted splicing alteration.
Sources
Not met · 5 · evaluated, threshold not reached
PM1 This variant is not located in a recognized mutational hotspot or well-established critical functional domain. Hotspot analysis confirms the residue is not statistically significant, and the synonymous change produces no amino acid alteration. Details ▾Hide ▴
Evidence considered
- Residue D157 is not in a statistically significant hotspot
- synonymous change with no functional domain disruption.
PP3 No in silico tools predict a deleterious effect. SpliceAI delta score is 0.00 (no splicing impact). REVEL and BayesDel scores are not available for this variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (no predicted splicing impact)
- REVEL and BayesDel not available.
Sources
PP5 ClinVar reports this variant as Likely benign, not pathogenic. PP5 requires a reputable source to have reported the variant as pathogenic. No expert panel or reputable source has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Likely benign (1 submitter)
- no pathogenic assertion from any reputable source.
Sources
BA1 Allele frequency in gnomAD is 0.002% (v2.1) and 0.001% (v4.1), well below the 1% threshold for BA1. Details ▾Hide ▴
Evidence considered
- gnomAD maximum observed AF = 0.00212% (v2.1)
- far below 1% BA1 threshold.
Sources
BS1 Allele frequency in gnomAD is 0.002% (v2.1) and 0.001% (v4.1), below the non-VCEP threshold of 0.3% for BS1. Details ▾Hide ▴
Evidence considered
- gnomAD maximum observed AF = 0.00847% (Admixed American subpopulation
- v2.1)
- below 0.3% BS1 threshold.
Sources
Not assessed · 12 · no assessment recorded
PS2 No de novo data are available for this variant in any reviewed source. Details ▾Hide ▴
Still missing
- No de novo testing or trio data available.
PS3 No well-established functional studies have been identified for this variant. OncoKB lists Unknown Oncogenic Effect with no supporting PMIDs for functional evidence. Details ▾Hide ▴
Still missing
- No functional assay data available for this specific variant.
PS4 No case-control prevalence data are available. The variant is observed at very low frequency in population databases (gnomAD), but no comparison of affected versus unaffected individuals has been performed. Details ▾Hide ▴
Still missing
- No case-control or cohort prevalence data.
PM6 No de novo data are available for this variant. PM6 requires confirmed de novo occurrence with confirmed maternity and paternity. Details ▾Hide ▴
Still missing
- No de novo data.
PP1 No segregation data are available for this variant. Details ▾Hide ▴
Still missing
- No family segregation data.
PP4 No patient phenotype data are available to assess specificity for a PRPF8-associated disorder. Details ▾Hide ▴
Still missing
- No phenotype data.
BS2 No homozygotes have been observed in gnomAD, and no data are available on co-occurrence with a known pathogenic variant in trans. Without observation in a healthy adult in a homozygous state or in trans with a pathogenic variant, BS2 cannot be applied. Details ▾Hide ▴
Still missing
- No homozygous observations
- no trans co-occurrence data.
BS3 No well-established functional studies demonstrate no damaging effect for this specific variant. Details ▾Hide ▴
Still missing
- No functional assay data.
BS4 No segregation data are available to assess non-segregation with disease. Details ▾Hide ▴
Still missing
- No family segregation data.
BP2 No data are available on co-occurrence of this variant in trans with a known pathogenic variant or in cis with a pathogenic variant in a recessive disorder gene. Details ▾Hide ▴
Still missing
- No co-occurrence data.
BP5 No data are available on an alternative molecular basis for disease in a case harboring this variant. Details ▾Hide ▴
Still missing
- No alternative molecular basis data.
PS5 No alternative causative variant has been identified at this locus. No published reports establish a different variant at c.471 as definitively pathogenic. Details ▾Hide ▴
Still missing
- No alternative pathogenic variant reported at this nucleotide position.
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_006445.3:c.471T>C is a synonymous variant (p.Asp157=) that does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for generic PVS1 application per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Synonymous variant with no predicted null effect on protein
- PVS1 decision framework does not apply.
Sources
PS1 N/APS1 applies when a different nucleotide change at the same position has been established as pathogenic and produces the same amino acid change. This is a synonymous variant with no amino acid change; no alternative nucleotide substitution at c.471 can produce a pathogenic missense with the same amino acid consequence. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- criterion not applicable.
PM3 N/APM3 applies to recessive disorders. PRPF8-associated disorders follow autosomal dominant inheritance. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants. This is a single-nucleotide synonymous substitution. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 requires a different missense change at the same residue that has been established as pathogenic. This is a synonymous variant (p.Asp157=) with no amino acid change; no same-residue missense comparator is relevant. PM5 candidate harvesting confirmed not applicable. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- PM5 semantics require a missense comparator.
PP2 N/APP2 applies to missense variants in a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. This is a synonymous variant (p.Asp157=), not a missense change. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- PP2 is restricted to missense variants.
BP1 N/ABP1 applies to missense variants in genes where only truncating variants cause disease. This is a synonymous variant (p.Asp157=), not a missense change. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- BP1 is restricted to missense variants.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions. This is a single-nucleotide synonymous substitution, not an in-frame indel. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- PRPF8
- Transcript
- NM_006445.3
- Coding (HGVS c.)
- NM_006445.3:c.471T>C
- Protein (HGVS p.)
- NP_006436.3:p.(Asp157=)
- GRCh38
- chr17:1682002 A>G
- GRCh37
- chr17:1585296 A>G
- ClinVar
- 1133865
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
17 / 1,613,606 alleles
AF 1.05e-05 · 0 homozygotes · FAF 5.29e-05
gnomAD v2.1
6 / 282,676 alleles
AF 2.12e-05 · 0 homozygotes · FAF 4.09e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.1e-05 · 17 / 1,613,606 alleles · 0 hom · FAF 5.3e-05
| African/African American8 / 74,758 | 0.00011 |
| Admixed American5 / 59,924 | 8.3e-05 |
| Remaining individuals1 / 62,484 | 1.6e-05 |
| European (non-Finnish)3 / 1,179,942 | 2.5e-06 |
0 alternate alleles recorded in 6 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 2.1e-05 · 6 / 282,676 alleles · 0 hom · FAF 4.1e-05
| Admixed American3 / 35,436 | 8.5e-05 |
| African/African American2 / 24,926 | 8e-05 |
| European (non-Finnish)1 / 129,062 | 7.7e-06 |
0 alternate alleles recorded in 5 other groups: Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.05354e-05; MAF= 0.00105%, 17/1613606 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000107012; MAF= 0.01070%, 8/74758 alleles, homozygotes = 0); grpmax FAF= 5.289e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.12257e-05; MAF= 0.00212%, 6/282676 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 8.46597e-05; MAF= 0.00847%, 3/35436 alleles, homozygotes = 0); grpmax FAF= 4.09e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingSpliceAI predicts no splicing impact for this synonymous variant (max delta score = 0.00). Multiple lines of computational evidence suggest no effect on the gene product. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- no predicted effect on splicing
- synonymous variant with no amino acid change.
Sources
BP7 SupportingThis is a synonymous variant (p.Asp157=) with SpliceAI delta score of 0.00, indicating no predicted impact on splicing. The nucleotide substitution is not predicted to affect mRNA processing. Details ▾Hide ▴
Evidence considered
- Synonymous variant at c.471T>C (p.Asp157=)
- SpliceAI max delta = 0.00
- no predicted splicing alteration.
Sources
PP3 No in silico tools predict a deleterious effect. SpliceAI delta score is 0.00 (no splicing impact). REVEL and BayesDel scores are not available for this variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (no predicted splicing impact)
- REVEL and BayesDel not available.
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 framework for refining ACMG-AMP variant classification criteria. NM_006445.3:c.471T>C 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
17 / 1,613,606 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
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/1133865/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-1585296-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-1682002-A-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-1682002-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006445.3%3Ac.471T…
- OncoKB ↗www.oncokb.org/gene/PRPF8/D157=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PRPF8+c.471T%3EC
- 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= 1.05354e-05; MAF= 0.00105%, 17/1613606 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000107012; MAF= 0.01070%, 8/74758 alleles, homozygotes = 0); grpmax FAF= 5.289e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.12257e-05; MAF= 0.00212%, 6/282676 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 8.46597e-05; MAF= 0.00847%, 3/35436 alleles, homozygotes = 0); grpmax FAF= 4.09e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 1133865)
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.