NM_015559.2:c.2953A>G

SETBP1 · NP_056374.2:p.(Ile985Val) · NM_015559.2

GRCh37: chr18:42532258 A>G · GRCh38: chr18:44952293 A>G

Gene: SETBP1 Transcript: NM_015559.2

Final call

VUS

PM2 supporting

Variant details

Gene

SETBP1

Transcript

NM_015559.2

Protein

NP_056374.2:p.(Ile985Val)

gnomAD AF

3.965903147687754e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

No functional studies, segregation data, de novo observations, case-control evidence, or authoritative pathogenic/benign classifications are available for this specific variant.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant (NP_056374.2:p.Ile985Val) that does not fall into null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants; PVS1 is not applicable per ClinGen SVI PVS1 decision tree.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not assessed	No evidence of a different nucleotide change at the same amino acid position (Ile985) with established pathogenicity was identified in the case evidence.
PS2	Not assessed	No de novo data were available for this variant in the case evidence; PS2 requires confirmed de novo occurrence with parental testing.
PS3	Not assessed	No functional studies were identified for NM_015559.2:c.2953A>G (p.Ile985Val). OncoKB reports unknown oncogenic effect with no variant-specific reviewed functional evidence; literature pass identified no functional studies for this variant.	oncokb
PS4	Not assessed	No case-control studies or statistical evidence for enrichment of this variant in affected individuals versus controls was identified.
PS5	Not assessed	No reputable source has classified this variant as definitively pathogenic. ClinVar shows conflicting interpretations of Uncertain Significance and Benign, each from single submitters without expert panel review.	clinvar
PM1	Not assessed	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.
PM2	Met	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 gnomad_v4 gnomad_canada
PM5	N/A	Unable to confirm classic same-residue PM5 semantics; no comparator missense variants at residue Ile985 were identified via candidate harvesting.	pm5_candidates
PM6	Not assessed	No de novo data were available for this variant; PM6 requires confirmed de novo occurrence without parental testing confirmation.
PP1	Not assessed	No segregation data were available for this variant; PP1 requires cosegregation with disease in multiple affected family members.
PP2	Not assessed	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	Not met	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. Multiple lines of computational evidence do not consistently support a deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	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	Not assessed	No reputable source has classified this variant as pathogenic. ClinVar submissions are conflicting (VUS and Benign) and neither represents an expert panel or multi-submitter consensus. No literature source definitively reports this variant as pathogenic.	clinvar
BA1	Not met	The allele frequency is far below the 1% BA1 threshold: gnomAD v4.1 total AF = 3.97×10⁻⁵ (0.004%). This variant is not a common polymorphism.	gnomad_v2 gnomad_v4
BS1	Not met	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. This variant is not present at a frequency expected for a standing benign variant.	gnomad_v2 gnomad_v4
BS2	Not assessed	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	Not assessed	No functional studies demonstrating no damaging effect on protein function or splicing were identified for this specific variant.
BS4	Not assessed	No segregation data demonstrating lack of cosegregation with disease were available.
BP1	N/A	SETBP1 is associated with both loss-of-function (SETBP1 haploinsufficiency disorder) and gain-of-function missense (Schinzel-Giedion syndrome) germline disease mechanisms. The gene has well-established pathogenic missense variants and is not one for which 'primarily truncating variants are known to cause disease.' BP1 is not applicable.	pvs1_gene_context
BP2	Not assessed	No data on observation of this variant in trans with a known pathogenic variant in a recessive disorder were available.
BP4	Not met	In silico predictions are mixed and do not consistently support no impact on the gene product. While BayesDel (0.050) and SpliceAI (0.00) predict a benign or neutral effect, REVEL (0.591) is in an intermediate range and does not clearly predict a benign effect. Multiple lines of computational evidence do not converge on a benign prediction.	revel bayesdel spliceai
BP5	Not assessed	No alternate molecular basis for disease was identified in this case; BP5 requires a plausible alternate cause for the observed phenotype.
BP6	Not assessed	ClinVar contains one benign submission (Labcorp/Invitae, single submitter) and one VUS submission (Ambry Genetics). A single-submitter benign classification does not meet the BP6 threshold of a reputable source reporting the variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splicing impact. This is a missense variant (c.2953A>G, p.Ile985Val) and BP7 is not applicable.

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