Classification rationale

PM2PP3 VUS

SETBP1 c.3023G>A

The SETBP1 c.3023G>A (p.Arg1008His) variant has been reported in ClinVar as Benign by a single clinical laboratory submitter.¹ 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.² 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 0.00.³

PM2 + PP3 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 revelbayesdelspliceai ↗

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.

Gene diagram · NM_015559.2 · variants mapped to exon structure

SETBP1 NM_015559.2

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 20 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting review Pathogenic

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.

gnomAD v2.1 total AF 5.658e-0516 alleles0 homozygotes

gnomad_v2 ↗gnomad_v4 ↗

PP3 supporting review Pathogenic

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.

REVEL 0.789BayesDel 0.412559SpliceAI max delta 0.00

spliceai ↗

Assessed · not applied · 4 not met · 16 not assessed

Pathogenic

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.

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.

PS3 No well-established functional study was identified for this exact variant that demonstrated a damaging effect.

PS4 No affected-case enrichment or case-control data were identified for this variant, so increased prevalence in affected individuals cannot be established.

PM1 Available hotspot evidence does not show p.Arg1008His lies in a statistically significant hotspot or other well-established critical region without benign variation.

PM3 No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease context.

PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant.

PP1 No segregation data were identified for this variant.

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.

PP4 No phenotype information was provided that would establish a highly specific SETBP1-related clinical presentation for this individual.

PP5 No reputable pathogenic classification was identified that should be used as stand-alone supporting evidence for this variant.

Benign

BA1 Population frequency does not meet the BA1 stand-alone benign threshold of 1%.

BS1 Population frequency does not exceed the non-VCEP BS1 threshold of 0.3%.

BS2 Available population data do not show convincing observation of this variant in healthy individuals in a manner sufficient to support BS2.

BS3 No well-established functional study was identified for this exact variant showing a normal or benign effect.

BS4 No nonsegregation data were identified for this variant.

BP2 No phase information or second-variant data were identified to evaluate BP2.

BP4 Available computational evidence does not support a benign interpretation.

BP5 No evidence was identified for an alternative molecular diagnosis that would explain the phenotype independently of this variant.

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.

N/A · 6 PVS1 · PM4 · PM5 · BP1 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

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.

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.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.004% · 64 / 1,613,926
0 hom · FAF 0.0088%

East Asian 8 / 44,834	0.018%
Middle Eastern 1 / 6,062	0.016%
African/African American 5 / 74,952	0.0067%
Remaining individuals 3 / 62,502	0.0048%
European (non-Finnish) 45 / 1,179,998	0.0038%
Admixed American 1 / 60,010	0.0017%
European (Finnish) 1 / 63,984	0.0016%

+ 3 not observed (Amish, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0057% · 16 / 282,768
0 hom · FAF 0.0047%

African/African American 4 / 24,968	0.016%
Remaining individuals 1 / 7,226	0.014%
European (non-Finnish) 11 / 129,078	0.0085%

+ 5 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (1 clinical laboratory). (ClinVarID = 1487300)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.789. BayesDel score = 0.412559.

SpliceAI ↗

Functional Unknown Oncogenic Effect

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.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99953114, n = 2 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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