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
PM2
SETBP1
c.2953A>G
p.Ile985Val
This variant
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 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 · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is extremely rare in population databases: gnomAD v2.1 allele frequency 1.41×10⁻⁵ (4/282,746 alleles, 0 homozygotes), gnomAD v4.1 allele frequency 3.97×10⁻⁵ (64/1,613,756 alleles, 0 homozygotes), with grpmax filtering allele frequency of 3.94×10⁻⁵. All frequencies are well below the 0.1% threshold for PM2 in non-VCEP generic ACMG/AMP application.
gnomAD v2.1: AF=1.41e-054/282746 alleles
Assessed · not applied
· 4 not met · 16 not assessed
Pathogenic
PS1
No evidence of a different nucleotide change at the same amino acid position (Ile985) with established pathogenicity was identified in the case evidence.
PS2
No de novo data were available for this variant in the case evidence; PS2 requires confirmed de novo occurrence with parental testing.
PS3
No functional studies were identified for NM_015559.2:c.2953A>G (p.Ile985Val).
PS4
No case-control studies or statistical evidence for enrichment of this variant in affected individuals versus controls was identified.
PM1
The variant does not lie in a statistically significant mutational hotspot and no evidence places residue 985 within a critical functional domain devoid of benign variation.
PM6
No de novo data were available for this variant; PM6 requires confirmed de novo occurrence without parental testing confirmation.
PP1
No segregation data were available for this variant; PP1 requires cosegregation with disease in multiple affected family members.
PP2
Missense constraint metrics (e.g., Z-score) for SETBP1 were not available in the case evidence; PP2 requires demonstration of a low rate of benign missense variation in the gene.
PP3
In silico predictions are mixed and do not converge on a deleterious effect: REVEL score 0.591 is in an intermediate range below typical pathogenic thresholds, BayesDel score 0.050 is strongly benign, and SpliceAI max delta is 0.00.
PP4
No phenotype specificity data were available; PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5
No reputable source has classified this variant as pathogenic.
Benign
BA1
The allele frequency is far below the 1% BA1 threshold: gnomAD v4.1 total AF = 3.97×10⁻⁵ (0.004%).
BS1
The allele frequency is below the 0.3% BS1 threshold: gnomAD v4.1 maximum subpopulation AF = 8.0×10⁻⁵ (0.008%) in Remaining individuals.
BS2
No data on observation of this variant in healthy adults were available for a disorder expected to be fully penetrant at an early age.
BS3
No functional studies demonstrating no damaging effect on protein function or splicing were identified for this specific variant.
BS4
No segregation data demonstrating lack of cosegregation with disease were available.
BP2
No data on observation of this variant in trans with a known pathogenic variant in a recessive disorder were available.
BP4
In silico predictions are mixed and do not consistently support no impact on the gene product.
BP5
No alternate molecular basis for disease was identified in this case; BP5 requires a plausible alternate cause for the observed phenotype.
BP6
ClinVar contains one benign submission (Labcorp/Invitae, single submitter) and one VUS submission (Ambry Genetics).
N/A · 4
PVS1 · PM5 · BP1 · BP7
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