NM_015559.2:c.3023G>A

SETBP1 · NP_056374.2:p.(Arg1008His) · NM_015559.2

GRCh37: chr18:42532328 G>A · GRCh38: chr18:44952363 G>A

Gene: SETBP1 Transcript: NM_015559.2

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

SETBP1

Transcript

NM_015559.2

Protein

NP_056374.2:p.(Arg1008His)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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

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.

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.

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, and the generic PVS1 scaffold does not place c.3023G>A (p.Arg1008His) in a nonsense, frameshift, or canonical ±1/2 splice category. Although SETBP1 loss of function is an established germline disease mechanism, that evidence does not make PVS1 applicable to this specific missense change.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No independently verified evidence was identified showing that this same amino acid change, p.Arg1008His, has already been established as pathogenic through a different nucleotide change.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.	clinvar
PS3	Not assessed	No well-established functional study was identified for this exact variant that demonstrated a damaging effect.	oncokb
PS4	Not assessed	No affected-case enrichment or case-control data were identified for this variant, so increased prevalence in affected individuals cannot be established.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	Available hotspot evidence does not show p.Arg1008His lies in a statistically significant hotspot or other well-established critical region without benign variation.	hotspots
PM2	Met	This variant is present at low frequency in population databases and remains below the non-VCEP PM2 threshold of 0.1%: gnomAD v2.1 AF is 0.0000566 (16/282768 alleles) and gnomAD v4.1 AF is 0.0000397 (64/1613926 alleles), with no homozygotes observed.	gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease context.
PM4	N/A	This is a missense substitution and does not produce a protein length change or in-frame exon-level alteration.
PM5	N/A	Same-residue PM5 was not applied because the retrieved review did not safely confirm that classic PM5 semantics should be used for this gene and variant context, and no validated comparator set was established.	pm5_candidates
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified for this variant.	clinvar
PP1	Not assessed	No segregation data were identified for this variant.
PP2	Not assessed	The retrieved evidence does not establish that SETBP1 is a gene in which pathogenic missense variation is sufficiently enriched and benign missense variation is sufficiently uncommon to support PP2 for this variant.
PP3	Met	Multiple computational predictors support a deleterious protein effect: REVEL is 0.789 and BayesDel is 0.412559. SpliceAI predicts no meaningful splice effect (max delta score 0.00), which does not offset the missense-damaging signal for this coding change.	revel bayesdel spliceai
PP4	Not assessed	No phenotype information was provided that would establish a highly specific SETBP1-related clinical presentation for this individual.
PP5	Not assessed	No reputable pathogenic classification was identified that should be used as stand-alone supporting evidence for this variant.	clinvar
BA1	Not met	Population frequency does not meet the BA1 stand-alone benign threshold of 1%. The highest observed overall frequency is 0.00566% in gnomAD v2.1 and 0.00397% in gnomAD v4.1, both far below 1%.	gnomad_v2 gnomad_v4
BS1	Not met	Population frequency does not exceed the non-VCEP BS1 threshold of 0.3%. The overall AF is 0.00566% in gnomAD v2.1 and 0.00397% in gnomAD v4.1, both below 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	Available population data do not show convincing observation of this variant in healthy individuals in a manner sufficient to support BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study was identified for this exact variant showing a normal or benign effect.	oncokb
BS4	Not assessed	No nonsegregation data were identified for this variant.
BP1	N/A	BP1 is not applicable because SETBP1 is not a gene in which only truncating variants are known to cause disease and missense variation is a recognized disease mechanism.	pvs1_gene_context
BP2	Not assessed	No phase information or second-variant data were identified to evaluate BP2.
BP3	N/A	BP3 is not applicable because this is not an in-frame deletion or insertion in a repetitive region.
BP4	Not met	Available computational evidence does not support a benign interpretation. REVEL (0.789) and BayesDel (0.412559) support a damaging missense effect, while SpliceAI only indicates that a splice effect is unlikely (max delta score 0.00).	revel bayesdel spliceai
BP5	Not assessed	No evidence was identified for an alternative molecular diagnosis that would explain the phenotype independently of this variant.
BP6	Not assessed	ClinVar includes a single benign submission for this variant, but that single non-expert assertion is not being used as stand-alone benign evidence here.	clinvar
BP7	N/A	BP7 is not applicable because this is not a synonymous or intronic variant.

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