Variant classification summary

NM_015559.2:c.575A>G

SETBP1 · NP_056374.2:p.(His192Arg) · NM_015559.2

GRCh37: chr18:42529880 A>G · GRCh38: chr18:44949915 A>G

Gene: SETBP1 Transcript: NM_015559.2

Final call

VUS

BP4 supporting

Variant details

Gene

SETBP1

Transcript

NM_015559.2

Protein

NP_056374.2:p.(His192Arg)

gnomAD AF

0.00010161820800007931 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 (Supporting): REVEL 0.101 is below the benign-supporting threshold (<=0.290), and SpliceAI max delta 0.028 predicts no splice disruption.

2

Overall classification: VUS — only one benign-supporting criterion (BP4) is met, and no pathogenic criterion reaches threshold, so the evidence is insufficient to move from uncertain significance.

Final determination: 1 supporting benign criterion alone does not meet any combining rule (needs BS+BP or 2BP for LB) → VUS.

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	Not applicable: this missense change is not a null variant (nonsense, frameshift, canonical splice, start-loss, or stop-loss), so no loss-of-function mechanism is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no alternate nucleotide change producing the identical p.(His192Arg) substitution with an established pathogenic classification was identified.	pm5_candidates
PS2	Not assessed	Not assessed: no de novo observation with confirmed parental testing is documented for this variant.	final_classification_framework
PS3	Not assessed	Not assessed: no functional assay data for p.(His192Arg) were available.
PS4	Not assessed	Not assessed: no case-control enrichment or phenotype-prevalence data for this variant were available.
PM1	Not met	Not met: cancerhotspots.org returned no result for SETBP1 H192, and no functional-domain annotation places residue 192 in a hotspot.	pvs1_gene_context
PM2	Not met	Not met: variant is present in gnomAD v4.1 (164/1,613,884 alleles; two homozygotes), so it is not absent from controls.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no affected-proband genotype, phase, or trans observation data were available.	generic_acmg_combination_rules
PM4	N/A	Not applicable: this missense change produces no protein length change, so there is nothing for PM4 to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no alternate pathogenic missense change at codon 192 (same-residue comparator) was identified.	pm5_candidates
PM6	Not assessed	Not assessed: no de novo occurrence without confirmed parental testing is documented.	final_classification_framework
PP1	Not assessed	Not assessed: no family history, affected relatives, or segregation data were provided.	final_classification_framework
PP2	Not assessed	Not assessed: no missense constraint metric (Z-score or o/e ratio) or authoritative gene-level statement was available.	pvs1_gene_context
PP3	Not met	Not met: REVEL 0.101 is below the pathogenic-supporting threshold (>=0.644), and SpliceAI max delta 0.028 predicts no splice disruption.	revel spliceai
PP4	Not assessed	Not assessed: no clinical phenotype findings specific to a SETBP1-related disorder were provided.
PP5	Not assessed	Not assessed: ClinVar contains no expert-panel submissions for this exact variant.	clinvar
BA1	Not met	Not met: highest subpopulation allele frequency 0.001636 (South Asian, gnomAD v4.1) is far below the 5% stand-alone benign threshold.	gnomad_v4 gnomad_v2
BS1	Not assessed	Not assessed: no validated maximum credible allele-frequency threshold is available to judge whether the South Asian frequency (0.001636) is too high.	gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: two gnomAD homozygotes are reported, but their healthy phenotype and SETBP1 penetrance are not established.	gnomad_v4
BS3	Not assessed	Not assessed: no functional assay demonstrating normal function for p.(His192Arg) was available.
BS4	Not assessed	Not assessed: no unaffected-carrier or non-segregation data are documented.	final_classification_framework
BP1	Not assessed	Not assessed: SETBP1 has both loss-of-function and gain-of-function missense disease mechanisms, and the condition under evaluation is unspecified.	pvs1_gene_context
BP2	Not assessed	Not assessed: no individual genotype, phase, or inheritance data were available to evaluate.	generic_acmg_combination_rules
BP3	N/A	Not applicable: this missense change does not alter protein length in a repetitive region, so there is nothing for BP3 to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): REVEL 0.101 is below the benign-supporting threshold (<=0.290), and SpliceAI max delta 0.028 predicts no splice impact.	revel spliceai
BP5	Not assessed	Not assessed: no documented alternate molecular diagnosis was available.
BP6	Not assessed	Not assessed: ClinVar has no expert-panel benign/likely-benign classification; only single-submitter laboratory assertions exist.	clinvar
BP7	N/A	Not applicable: this variant is missense, not synonymous, so BP7's silent-variant premise does not hold.	generic_acmg_combination_rules

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.