NM_015559.2:c.2953A>G (p.Ile985Val) in SETBP1 is absent from or extremely rare in large population cohorts (gnomAD v4.1 AF = 3.97×10⁻⁵), meeting PM2 at a supporting level.1 This is a missense variant; PVS1 is not applicable because it does not fall into null-variant categories. In silico predictions are mixed: REVEL is intermediate (0.591), BayesDel is benign (0.050), and SpliceAI predicts no splicing impact (delta = 0.00), so neither PP3 nor BP4 is met.2 No functional studies, segregation data, de novo observations, case-control evidence, or authoritative pathogenic/benign classifications are available for this specific variant.3 With only one supporting-level pathogenic criterion (PM2_Supporting) and no benign criteria met, this variant is classified as a Variant of Uncertain Significance under generic ACMG/AMP 2015 rules.4
SETBP1
Final classification
VUS
SETBP1 c.2953A>G · p.Ile985Val
SETBP1
NM_015559.2:c.2953A>G (p.Ile985Val) in SETBP1 is absent from or extremely rare in large population cohorts (gnomAD v4.1 AF = 3.97×10⁻⁵), meeting PM2 at a supporting level.
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; combination = 1 supporting, which maps to VUS.
Classification rationale
PM2
VUS
SETBP1 c.2953A>G
PM2
→
VUS
2
revelbayesdelspliceai ↗pvs1_variant_assessment
4
generic_acmg_combination_rules
Gene diagram
· NM_015559.2 · variants mapped to exon structure
SETBP1
NM_015559.2
Fetching transcript structure from UCSC…
Applied criteria · 1 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= 3.9659e-05; MAF= 0.00397%, 64/1613756 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 8.00205e-05; MAF= 0.00800%, 5/62484 alleles, homozygotes = 0); grpmax FAF= 3.937e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.4147e-05; MAF= 0.00141%, 4/282746 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000138427; MAF= 0.01384%, 1/7224 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.004%
· 64 / 1,613,756
0 hom · FAF 0.0039%
0 hom · FAF 0.0039%
Remaining individuals 5 / 62,484 |
0.008% |
European (non-Finnish) 59 / 1,179,978 |
0.005% |
+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0014%
· 4 / 282,746
0 hom · FAF 0.00029%
0 hom · FAF 0.00029%
Remaining individuals 1 / 7,224 |
0.014% |
European (non-Finnish) 3 / 129,080 |
0.0023% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 1474529)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.591. BayesDel score = 0.0498507.
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 6 PMIDs not cited in assessment
25626707 ↗
Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.
CLINVAR
23037933 ↗
Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.
CLINVAR
24394680 ↗
Parental permission for pilot newborn screening research: guidelines from the NBSTRN.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR
31022120 ↗
ACOG Committee Opinion No. 778 Summary: Newborn Screening and the Role of the Obstetrician-Gynecologist.
CLINVAR