NM_015559.2:c.1313C>A

SETBP1 · NP_056374.2:p.(Ala438Asp) · NM_015559.2

GRCh37: chr18:42530618 C>A · GRCh38: chr18:44950653 C>A

Gene: SETBP1 Transcript: NM_015559.2

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

SETBP1

Transcript

NM_015559.2

Protein

NP_056374.2:p.(Ala438Asp)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The SETBP1 c.1313C>A (p.Ala438Asp) variant has not been reported in ClinVar, and no variant-specific reviewed functional evidence was identified in OncoKB.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0 and is below the 0.1% threshold used for PM2 support.

Computational evidence does not support a damaging effect: REVEL is 0.054, BayesDel is -0.44775, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, supporting BP4 rather than PP3.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

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	Not met	This variant is a missense substitution, p.(Ala438Asp), and does not fall within the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants. Although SETBP1 loss of function is an established germline disease mechanism, the generic PVS1 framework does not apply to this variant type.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified showing that this nucleotide change results in the same amino acid substitution as a previously established pathogenic variant.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with parental confirmation was identified for this variant.	clinvar
PS3	Not assessed	No published functional study directly testing p.(Ala438Asp) was identified, so available evidence does not support a well-established damaging functional effect for this specific variant.	oncokb
PS4	Not assessed	No case series, odds ratio, or count of independent affected individuals was identified for this variant, so enrichment in affected individuals has not been established.	clinvar
PM1	Not met	This variant was not identified in a statistically significant hotspot, and no validated critical functional domain without benign variation was established at residue Ala438 from the available evidence.	hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0 and is below the PM2 threshold of 0.1% for rare-variant support.	gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic variant in an affected individual.	clinvar
PM4	Not met	This variant is a single amino acid substitution and does not change protein length or create an in-frame insertion or deletion.
PM5	Not assessed	No evidence was identified showing a different pathogenic missense substitution at the same residue, Ala438.	clinvar
PM6	Not assessed	No presumed de novo occurrence without full parental confirmation was identified for this variant.	clinvar
PP1	Not assessed	No segregation data were identified for this variant in affected family members.	clinvar
PP2	Not assessed	Available evidence does not establish that pathogenic missense variation is a sufficiently predominant disease mechanism across SETBP1 to apply PP2 to this non-hotspot missense change.	pvs1_gene_context
PP3	Not met	Available computational evidence does not support a damaging effect. REVEL is 0.054, BayesDel is -0.44775, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.	revel bayesdel spliceai
PP4	Not assessed	No phenotype information was provided that is sufficiently specific for a single genetic etiology to support PP4.
PP5	Not assessed	No reputable source classification supporting pathogenicity was identified for this variant.	clinvar oncokb
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0 and is below the BA1 threshold of 1%.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0 and is below the BS1 threshold of 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals for a condition expected to be fully penetrant at an early age.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study showing a normal or benign effect for p.(Ala438Asp) was identified.	oncokb
BS4	Not assessed	No family data were identified showing lack of segregation between this variant and disease.	clinvar
BP1	N/A	BP1 does not apply because SETBP1 has an established pathogenic missense disease mechanism, so missense variation is not a class that is generally expected to be benign in this gene.	pvs1_gene_context
BP2	Not assessed	No phase information was identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.	clinvar
BP3	Not assessed	No evidence was identified showing that this variant lies within a repetitive region without a known function.
BP4	Met	Computational evidence supports no damaging effect. REVEL is 0.054, BayesDel is -0.44775, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which together support a benign computational interpretation.	revel bayesdel spliceai
BP5	Not assessed	No alternate molecular diagnosis or other established cause was provided to explain the phenotype independently of this variant.
BP6	Not assessed	No reputable source classification supporting benignity was identified for this variant.	clinvar
BP7	N/A	BP7 does not apply because this variant is missense, not a synonymous or deep intronic change.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.