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 ↗

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

SETBP1 NM_015559.2

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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