About SETBP1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SETBP1 c.1313C>A, p.(Ala438Asp)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0 and is below the PM2 threshold of 0.1% for rare-variant support.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Computational evidence supports no damaging effect. REVEL is 0.054, BayesDel is -0.44775, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which together support a benign computational interpretation.
Recorded classification: Uncertain significance
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; combination = 1 supporting + 1 supporting benign, which maps to VUS because the evidence is conflicting.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SETBP1, an epigenetic remodeling protein, is frequently altered by mutation in a range of hematopoietic malignancies.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
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.
28 criteria with recorded statuses: 2 met · 6 not met · 18 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The SETBP1 c.1313C>A (p.Ala438Asp) variant has not been reported in ClinVar, and no variant-specific reviewed functional evidence was identified in OncoKB.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0 and is below the 0.1% threshold used for PM2 support.
Computational evidence does not support a damaging effect: REVEL is 0.054, BayesDel is -0.44775, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, supporting BP4 rather than PP3.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0 and is below the PM2 threshold of 0.1% for rare-variant support. Details ▾Hide ▴
BP4 SupportingComputational evidence supports no damaging effect. REVEL is 0.054, BayesDel is -0.44775, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which together support a benign computational interpretation. Details ▾Hide ▴
Evidence considered
- REVEL 0.054
- BayesDel -0.44775
- SpliceAI max delta 0.00
Sources
Not met · 6 · evaluated, threshold not reached
PVS1 This variant is a missense substitution, p.(Ala438Asp), and does not fall within the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants. Although SETBP1 loss of function is an established germline disease mechanism, the generic PVS1 framework does not apply to this variant type. Details ▾Hide ▴
Rule
Generic ClinGen SVI PVS1 recommendations for null variants
Evidence considered
- SETBP1 loss-of-function mechanism supported at the gene level
- Variant scaffold classified this change as outside generic PVS1 null-variant buckets
Sources
PM1 This variant was not identified in a statistically significant hotspot, and no validated critical functional domain without benign variation was established at residue Ala438 from the available evidence. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots review did not show a significant hotspot at A438
Still missing
- Regional disease-clustering or functional-domain evidence specific to Ala438 remains limited
Sources
PM4 This variant is a single amino acid substitution and does not change protein length or create an in-frame insertion or deletion. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.(Ala438Asp)
PP3 Available computational evidence does not support a damaging effect. REVEL is 0.054, BayesDel is -0.44775, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Evidence considered
- REVEL 0.054
- BayesDel -0.44775
- SpliceAI max delta 0.00
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0 and is below the BA1 threshold of 1%. Details ▾Hide ▴
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0 and is below the BS1 threshold of 0.3%. Details ▾Hide ▴
Not assessed · 18 · no assessment recorded
PS1 No evidence was identified showing that this nucleotide change results in the same amino acid substitution as a previously established pathogenic variant. Details ▾Hide ▴
Evidence considered
- ClinVar search did not identify this variant
Still missing
- Need confirmed pathogenic comparison variants causing the same amino acid change
Sources
PS2 No confirmed de novo occurrence with parental confirmation was identified for this variant. Details ▾Hide ▴
Evidence considered
- No ClinVar record or de novo note identified
Still missing
- Need a case report or laboratory record documenting confirmed de novo occurrence with phenotype specificity
Sources
PS3 No published functional study directly testing p.(Ala438Asp) was identified, so available evidence does not support a well-established damaging functional effect for this specific variant. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence
Still missing
- Need a validated functional assay directly evaluating p.(Ala438Asp)
Sources
PS4 No case series, odds ratio, or count of independent affected individuals was identified for this variant, so enrichment in affected individuals has not been established. Details ▾Hide ▴
Evidence considered
- ClinVar search was negative for the exact variant
Still missing
- Need independent affected observations or formal case-control enrichment data for the exact variant
Sources
PM3 No evidence was identified showing this variant in trans with a pathogenic variant in an affected individual. Details ▾Hide ▴
Evidence considered
- No case-level database record identified
Still missing
- Need phase-confirmed trans observations in affected individuals if relevant
Sources
PM5 No evidence was identified showing a different pathogenic missense substitution at the same residue, Ala438. Details ▾Hide ▴
Evidence considered
- ClinVar search was negative for the exact variant
Still missing
- Need established pathogenic missense variants affecting the same codon
Sources
PM6 No presumed de novo occurrence without full parental confirmation was identified for this variant. Details ▾Hide ▴
Evidence considered
- No ClinVar record or de novo note identified
Still missing
- Need a proband report describing de novo occurrence without complete parental confirmation
Sources
PP1 No segregation data were identified for this variant in affected family members. Details ▾Hide ▴
Evidence considered
- No family-based record identified
Still missing
- Need informative family segregation data
Sources
PP2 Available evidence does not establish that pathogenic missense variation is a sufficiently predominant disease mechanism across SETBP1 to apply PP2 to this non-hotspot missense change. Details ▾Hide ▴
Evidence considered
- SETBP1 has multiple disease mechanisms
- including loss of function and hotspot missense effects
Still missing
- Need gene-specific evidence supporting PP2 for SETBP1 outside the known hotspot context
Sources
pvs1_gene_context
PP4 No phenotype information was provided that is sufficiently specific for a single genetic etiology to support PP4. Details ▾Hide ▴
Still missing
- Need phenotype data with diagnostic specificity
PP5 No reputable source classification supporting pathogenicity was identified for this variant. Details ▾Hide ▴
BS2 No evidence was identified showing this variant in healthy adult individuals for a condition expected to be fully penetrant at an early age. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
Still missing
- Need confirmed observations in appropriately phenotyped unaffected individuals
Sources
BS3 No well-established functional study showing a normal or benign effect for p.(Ala438Asp) was identified. Details ▾Hide ▴
Evidence considered
- No variant-specific reviewed functional evidence identified
Still missing
- Need a validated functional assay showing no damaging effect for this specific variant
Sources
BS4 No family data were identified showing lack of segregation between this variant and disease. Details ▾Hide ▴
Evidence considered
- No family-based record identified
Still missing
- Need informative non-segregation evidence
Sources
BP2 No phase information was identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant. Details ▾Hide ▴
Evidence considered
- No case-level phase data identified
Still missing
- Need phase data with another pathogenic variant
Sources
BP3 No evidence was identified showing that this variant lies within a repetitive region without a known function. Details ▾Hide ▴
Still missing
- Need region-specific annotation supporting a repetitive nonfunctional context
BP5 No alternate molecular diagnosis or other established cause was provided to explain the phenotype independently of this variant. Details ▾Hide ▴
Still missing
- Need confirmed alternative cause of disease
BP6 No reputable source classification supporting benignity was identified for this variant. Details ▾Hide ▴
Evidence considered
- ClinVar search was negative for the exact variant
Still missing
- Need an established external benign classification source if BP6 is to be considered
Sources
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
BP1 N/ABP1 does not apply because SETBP1 has an established pathogenic missense disease mechanism, so missense variation is not a class that is generally expected to be benign in this gene. Details ▾Hide ▴
Evidence considered
- SETBP1 disease mechanisms include pathogenic missense as well as loss of function
Sources
pvs1_gene_context
BP7 N/ABP7 does not apply because this variant is missense, not a synonymous or deep intronic change. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.(Ala438Asp)
Identifiers
- Gene
- SETBP1
- Transcript
- NM_015559.2
- Coding (HGVS c.)
- NM_015559.2:c.1313C>A
- Protein (HGVS p.)
- NP_056374.2:p.(Ala438Asp)
- GRCh38
- chr18:44950653 C>A
- GRCh37
- chr18:42530618 C>A
Gene diagram
Every interpreted variant in SETBP1, mapped onto the exon structure of NM_015559.2. Select a row to find it on the plot.
SETBP1NM_015559.2
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 SETBP1
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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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingComputational evidence supports no damaging effect. REVEL is 0.054, BayesDel is -0.44775, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which together support a benign computational interpretation. Details ▾Hide ▴
Evidence considered
- REVEL 0.054
- BayesDel -0.44775
- SpliceAI max delta 0.00
Sources
PP3 Available computational evidence does not support a damaging effect. REVEL is 0.054, BayesDel is -0.44775, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Evidence considered
- REVEL 0.054
- BayesDel -0.44775
- SpliceAI max delta 0.00
Sources
BP7 N/ABP7 does not apply because this variant is missense, not a synonymous or deep intronic change. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.(Ala438Asp)
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.054. BayesDel score = -0.44775.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
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/?term=NM_015559.2%3Ac.1313C%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/18-42530618-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr18-44950653-C-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_015559.2%3Ac.1313…
- OncoKB ↗www.oncokb.org/gene/SETBP1/A438D
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=SETBP1+c.1313C%3EA
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.054. BayesDel score = -0.44775.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SETBP1, an epigenetic remodeling protein, is frequently altered by mutation in a range of hematopoietic malignancies.
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.