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LYFE SCIENCES
Project: HERA
NM_015559.2:c.3023G>A
p.Arg1008His  ·  SETBP1
ACMG/AMP
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Classification rationale
1

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

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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.
gnomAD v4.1This 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 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Benign (1 clinical laboratory). (ClinVarID = 1487300)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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 ↗
In silico evidence
04
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 ↗
COSMIC evidence
05
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).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueR1008
Hotspots ↗