About SETBP1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SETBP1 c.3023G>A, p.(Arg1008His)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
This variant is present at low frequency in population databases and remains below the non-VCEP PM2 threshold of 0.1%: gnomAD v2.1 AF is 0.0000566 (16/282768 alleles) and gnomAD v4.1 AF is 0.0000397 (64/1613926 alleles), with no homozygotes observed.
PP3Supporting
PP3 · supporting
Multiple computational predictors support a deleterious protein effect: REVEL is 0.789 and BayesDel is 0.412559. SpliceAI predicts no meaningful splice effect (max delta score 0.00), which does not offset the missense-damaging signal for this coding change.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
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, PP3 supporting; combination = 2 supporting, which maps to VUS.
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
64 / 1,613,926 alleles
gnomAD v4.1: 64 / 1,613,926 alleles. Recorded AF 3.96549e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 5.65835e-05; MAF= 0.00566%, 16/282768 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000160205; MAF= 0.01602%, 4/24968 alleles, homozygotes = 0); grpmax FAF= 4.739e-05.
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 · 4 not met · 16 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
The SETBP1 c.3023G>A (p.Arg1008His) variant has been reported in ClinVar as Benign by a single clinical laboratory submitter.
This variant is present at low frequency in population databases, with gnomAD v2.1 AF 0.0000566 (16/282768 alleles) and gnomAD v4.1 AF 0.0000397 (64/1613926 alleles), both below the 0.1% PM2 threshold and below BS1 and BA1 benign thresholds.
Computational evidence supports a deleterious missense effect, with REVEL 0.789 and BayesDel 0.412559, while SpliceAI predicts no significant splice impact with a max delta score of 0.00.
No criteria match.
Met · 2
PM2 SupportingThis variant is present at low frequency in population databases and remains below the non-VCEP PM2 threshold of 0.1%: gnomAD v2.1 AF is 0.0000566 (16/282768 alleles) and gnomAD v4.1 AF is 0.0000397 (64/1613926 alleles), with no homozygotes observed. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 total AF 5.658e-05
- 16 alleles
- 0 homozygotes
- gnomAD v4.1 total AF 3.965e-05
- 64 alleles
Sources
PP3 SupportingMultiple computational predictors support a deleterious protein effect: REVEL is 0.789 and BayesDel is 0.412559. SpliceAI predicts no meaningful splice effect (max delta score 0.00), which does not offset the missense-damaging signal for this coding change. Details ▾Hide ▴
Evidence considered
- REVEL 0.789
- BayesDel 0.412559
- SpliceAI max delta 0.00
Sources
Not met · 4 · evaluated, threshold not reached
PM1 Available hotspot evidence does not show p.Arg1008His lies in a statistically significant hotspot or other well-established critical region without benign variation. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots did not identify a significant hotspot at residue R1008
Still missing
- Cancer Hotspots review for this residue was flagged for human review despite no hotspot row being identified.
Sources
BA1 Population frequency does not meet the BA1 stand-alone benign threshold of 1%. The highest observed overall frequency is 0.00566% in gnomAD v2.1 and 0.00397% in gnomAD v4.1, both far below 1%. Details ▾Hide ▴
BS1 Population frequency does not exceed the non-VCEP BS1 threshold of 0.3%. The overall AF is 0.00566% in gnomAD v2.1 and 0.00397% in gnomAD v4.1, both below 0.3%. Details ▾Hide ▴
BP4 Available computational evidence does not support a benign interpretation. REVEL (0.789) and BayesDel (0.412559) support a damaging missense effect, while SpliceAI only indicates that a splice effect is unlikely (max delta score 0.00). Details ▾Hide ▴
Evidence considered
- REVEL 0.789
- BayesDel 0.412559
- SpliceAI max delta 0.00
Sources
Not assessed · 16 · no assessment recorded
PS1 No independently verified evidence was identified showing that this same amino acid change, p.Arg1008His, has already been established as pathogenic through a different nucleotide change. Details ▾Hide ▴
Evidence considered
- ClinVar exact-variant record only
Still missing
- No same-amino-acid pathogenic comparator was identified in the retrieved sources.
Sources
PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant. Details ▾Hide ▴
Evidence considered
- No de novo information was available in the retrieved record set
Still missing
- No case-level inheritance data were identified for p.Arg1008His.
Sources
PS3 No well-established functional study was identified for this exact variant that demonstrated a damaging effect. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence
Still missing
- No exact-variant functional assay data were identified.
Sources
PS4 No affected-case enrichment or case-control data were identified for this variant, so increased prevalence in affected individuals cannot be established. Details ▾Hide ▴
Evidence considered
- Single ClinVar benign submission
- Low-frequency population observations in gnomAD
Still missing
- No exact-variant case series or enrichment data were identified.
Sources
PM3 No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease context. Details ▾Hide ▴
Still missing
- No allelic phase or recessive case data were identified.
PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant. Details ▾Hide ▴
Evidence considered
- No inheritance data available in retrieved sources
Still missing
- No case-level de novo information was identified.
Sources
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Still missing
- No family-based cosegregation reports were identified.
PP2 The retrieved evidence does not establish that SETBP1 is a gene in which pathogenic missense variation is sufficiently enriched and benign missense variation is sufficiently uncommon to support PP2 for this variant. Details ▾Hide ▴
Still missing
- No gene-level missense-rate framework was identified for PP2.
PP4 No phenotype information was provided that would establish a highly specific SETBP1-related clinical presentation for this individual. Details ▾Hide ▴
Still missing
- No case phenotype was available for phenotype-specific assessment.
PP5 No reputable pathogenic classification was identified that should be used as stand-alone supporting evidence for this variant. Details ▾Hide ▴
Evidence considered
- ClinVar reports a benign rather than pathogenic assertion
Sources
BS2 Available population data do not show convincing observation of this variant in healthy individuals in a manner sufficient to support BS2. Details ▾Hide ▴
Evidence considered
- No homozygotes observed in gnomAD
Still missing
- No unaffected adult enrichment or other BS2-style evidence was identified.
Sources
BS3 No well-established functional study was identified for this exact variant showing a normal or benign effect. Details ▾Hide ▴
Evidence considered
- No variant-specific reviewed functional evidence identified
Still missing
- No exact-variant benign functional assay data were identified.
Sources
BS4 No nonsegregation data were identified for this variant. Details ▾Hide ▴
Still missing
- No informative pedigree data were identified.
BP2 No phase information or second-variant data were identified to evaluate BP2. Details ▾Hide ▴
Still missing
- No allelic phase data were identified.
BP5 No evidence was identified for an alternative molecular diagnosis that would explain the phenotype independently of this variant. Details ▾Hide ▴
Still missing
- No case-level alternate diagnosis data were available.
BP6 ClinVar includes a single benign submission for this variant, but that single non-expert assertion is not being used as stand-alone benign evidence here. Details ▾Hide ▴
Evidence considered
- ClinVar benign classification from one clinical laboratory
Sources
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and the generic PVS1 scaffold does not place c.3023G>A (p.Arg1008His) in a nonsense, frameshift, or canonical ±1/2 splice category. Although SETBP1 loss of function is an established germline disease mechanism, that evidence does not make PVS1 applicable to this specific missense change. Details ▾Hide ▴
Evidence considered
- SETBP1 loss of function is supported as a germline disease mechanism
- Variant-level PVS1 scaffold indicates the change is outside generic null-variant PVS1 buckets
Sources
PM4 N/AThis is a missense substitution and does not produce a protein length change or in-frame exon-level alteration. Details ▾Hide ▴
Evidence considered
- Protein consequence p.Arg1008His
PM5 N/ASame-residue PM5 was not applied because the retrieved review did not safely confirm that classic PM5 semantics should be used for this gene and variant context, and no validated comparator set was established. Details ▾Hide ▴
Evidence considered
- PM5 candidate review marked classic same-residue PM5 as not safely confirmable
Still missing
- No confirmed same-residue pathogenic or likely pathogenic comparator framework was identified.
Sources
pm5_candidates
BP1 N/ABP1 is not applicable because SETBP1 is not a gene in which only truncating variants are known to cause disease and missense variation is a recognized disease mechanism. Details ▾Hide ▴
Evidence considered
- SETBP1 disease mechanisms include non-truncating pathogenic variation
Sources
pvs1_gene_context
BP3 N/ABP3 is not applicable because this is not an in-frame deletion or insertion in a repetitive region. Details ▾Hide ▴
Evidence considered
- Protein consequence p.Arg1008His
BP7 N/ABP7 is not applicable because this is not a synonymous or intronic variant. Details ▾Hide ▴
Evidence considered
- Coding missense change p.Arg1008His
Identifiers
- Gene
- SETBP1
- Transcript
- NM_015559.2
- Coding (HGVS c.)
- NM_015559.2:c.3023G>A
- Protein (HGVS p.)
- NP_056374.2:p.(Arg1008His)
- GRCh38
- chr18:44952363 G>A
- GRCh37
- chr18:42532328 G>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
64 / 1,613,926 alleles
AF 3.97e-05 · 0 homozygotes · FAF 8.84e-05
gnomAD v2.1
16 / 282,768 alleles
AF 5.66e-05 · 0 homozygotes · FAF 4.74e-05
By genetic ancestry
gnomAD v4.1
AF 4e-05 · 64 / 1,613,926 alleles · 0 hom · FAF 8.8e-05
| East Asian8 / 44,834 | 0.00018 |
| Middle Eastern1 / 6,062 | 0.00016 |
| African/African American5 / 74,952 | 6.7e-05 |
| Remaining individuals3 / 62,502 | 4.8e-05 |
| European (non-Finnish)45 / 1,179,998 | 3.8e-05 |
| Admixed American1 / 60,010 | 1.7e-05 |
| European (Finnish)1 / 63,984 | 1.6e-05 |
0 alternate alleles recorded in 3 other groups: Amish, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 5.7e-05 · 16 / 282,768 alleles · 0 hom · FAF 4.7e-05
| African/African American4 / 24,968 | 0.00016 |
| Remaining individuals1 / 7,226 | 0.00014 |
| European (non-Finnish)11 / 129,078 | 8.5e-05 |
0 alternate alleles recorded in 5 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.96549e-05; MAF= 0.00397%, 64/1613926 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000178436; MAF= 0.01784%, 8/44834 alleles, homozygotes = 0); grpmax FAF= 8.843e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 5.65835e-05; MAF= 0.00566%, 16/282768 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000160205; MAF= 0.01602%, 4/24968 alleles, homozygotes = 0); grpmax FAF= 4.739e-05.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingMultiple computational predictors support a deleterious protein effect: REVEL is 0.789 and BayesDel is 0.412559. SpliceAI predicts no meaningful splice effect (max delta score 0.00), which does not offset the missense-damaging signal for this coding change. Details ▾Hide ▴
Evidence considered
- REVEL 0.789
- BayesDel 0.412559
- SpliceAI max delta 0.00
Sources
BP4 Available computational evidence does not support a benign interpretation. REVEL (0.789) and BayesDel (0.412559) support a damaging missense effect, while SpliceAI only indicates that a splice effect is unlikely (max delta score 0.00). Details ▾Hide ▴
Evidence considered
- REVEL 0.789
- BayesDel 0.412559
- SpliceAI max delta 0.00
Sources
BP7 N/ABP7 is not applicable because this is not a synonymous or intronic variant. Details ▾Hide ▴
Evidence considered
- Coding missense change p.Arg1008His
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.789. BayesDel score = 0.412559.
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
64 / 1,613,926 recorded alleles
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/variation/1487300/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/18-42532328-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr18-44952363-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_015559.2%3Ac.3023…
- OncoKB ↗www.oncokb.org/gene/SETBP1/R1008H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=107420872
- 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= 3.96549e-05; MAF= 0.00397%, 64/1613926 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000178436; MAF= 0.01784%, 8/44834 alleles, homozygotes = 0); grpmax FAF= 8.843e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 5.65835e-05; MAF= 0.00566%, 16/282768 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000160205; MAF= 0.01602%, 4/24968 alleles, homozygotes = 0); grpmax FAF= 4.739e-05.
ClinVar
This variant has been reported in ClinVar as Benign (1 clinical laboratory). (ClinVarID = 1487300)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.789. BayesDel score = 0.412559.
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 previously been reported in somatic cancers (COSMIC; COSV99953114, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.