Variant classification summary

NM_015559.3:c.2602G>A

SETBP1 · NP_056374.2:p.(Asp868Asn) · NM_015559.3

GRCh37: chr18:42531907 G>A · GRCh38: chr18:44951942 G>A

Gene: SETBP1 Transcript: NM_015559.3

Final call

Pathogenic

PS1 strong PS2 strong PS3 strong PS4 strong PM1 moderate PM2 supporting

Variant details

Gene

SETBP1

Transcript

NM_015559.3

Protein

NP_056374.2:p.(Asp868Asn)

gnomAD AF

3.09815065191286e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS1 strong supports the identical previously established pathogenic p.Asp868Asn change.

2

Pathogenic: PS2 strong supports confirmed de novo occurrence in four affected patients.

3

Pathogenic: PS3 strong supports damaging gain-of-function effects in complementary exact-variant assays.

4

Pathogenic: PS4 strong supports marked enrichment in affected individuals versus controls.

5

Pathogenic: PM1 moderate places Asp868 in the established SETBP1 disease-associated hotspot.

6

Pathogenic: PM2 supporting reflects the extremely low gnomAD v4.1 filtering allele frequency.

Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria satisfy the Pathogenic rule; PS1, PS2, PS3, and PS4 provide four strong criteria, with additional PM1 moderate and PM2 supporting evidence.

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: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Met	Met: the identical SETBP1 p.Asp868Asn change was previously reported in four affected individuals and is Pathogenic in ClinVar variation 1032.	clinvar PMID:20436468 PMID:25741868
PS2	Met	Met: G2602A/p.D868N was de novo in four affected patients, with parentage confirmed by short tandem repeat analysis in all available case-parent trios.	PMID:20436468
PS3	Met	Met, strong: HEK293, patient-fibroblast, and murine progenitor assays consistently showed increased SETBP1 stability, proliferation, or immortalization for exact D868N.	PMID:28346496 PMID:23832012
PS4	Met	Met: exact variant occurred in 4/13 affected individuals versus 0/94 controls; continuity-corrected OR=89.53 with 95% CI 4.47-1792.77, exceeding 5 and excluding 1.	PMID:20436468 gnomad_v4
PM1	Met	Met: Asp868 lies within the established SETBP1 Glu858-Ile871 hotspot, while gnomAD v4.1 shows AF 3.09815e-06 and zero homozygotes.	PMID:23222956 PMID:28346496 gnomad_v4 PMID:25741868
PM2	Met	Met at supporting: gnomAD v4.1 AF is 3.09815e-06 and grpmax FAF is 1.24e-06, both below the PM2 threshold of 0.0001.	gnomad_v4 gnomad_v2 PMID:25741868
PM3	N/A	Not applicable: SETBP1-related Schinzel-Giedion syndrome is autosomal dominant, whereas PM3 is restricted to recessive disorders.	PMID:25663181 PMID:20436468
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different pathogenic missense substitution at SETBP1 residue Asp868 was established in the available evidence.	pm5_candidates PMID:23222956 PMID:28346496 PMID:25741868
PM6	Not met	Not met: Parentage was confirmed in all available case-parent trios, so the variant is not merely assumed de novo without parental confirmation.	PMID:20436468
PP1	N/A	Not applicable: The variant was recurrently de novo, with no multiple affected family members providing informative cosegregation data.	PMID:20436468
PP2	Not assessed	Not assessed: missense disease mechanisms are documented, but no validated SETBP1 benign-missense rate is available for the required PP2 combination.	PMID:20436468 PMID:23222956 PMID:28346496 PMID:25741868
PP3	Not met	Not met: missense REVEL is 0.476, below the generic PP3 supporting threshold of 0.644.	revel
PP4	Not assessed	Not assessed: the patient's phenotype and family history are not documented sufficiently to determine whether they are highly specific for a single-gene disease.
PP5	Not met	Not met: ClinVar has zero exact-variant expert-panel submissions, so ordinary Pathogenic laboratory assertions cannot trigger PP5.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 1.24e-06, far below the generic BA1 threshold of 0.05.	gnomad_v4 gnomad_v2 clinvar PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 1.24e-06, below the generic BS1 threshold of 0.01 and not supported by a higher credible disease frequency.	gnomad_v4 gnomad_v2 PMID:25741868
BS2	Not assessed	Not assessed: gnomAD v4.1 reports zero homozygotes, but no documented healthy adult carrying the variant is available for the BS2 rule.	gnomad_v4 gnomad_v2
BS3	Not met	Not met: exact D868N assays showed increased SETBP1 stability and cellular growth, with no study demonstrating normal protein function or splicing.	PMID:28346496 PMID:23832012 PMID:23222956 PMID:20436468
BS4	Not assessed	Not assessed: No affected relatives were reported as tested noncarriers, so lack of segregation cannot be evaluated.	PMID:20436468
BP1	Not met	Not met: SETBP1 has a documented recurrent missense gain-of-function mechanism, including p.Asp868Asn, rather than primarily truncating disease.	PMID:20436468 PMID:23222956 PMID:28346496 PMID:25741868
BP2	Not assessed	Not assessed: affected individuals had heterozygous de novo D868N, but no pathogenic second allele or cis/trans phase observation was reported.	PMID:20436468
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL is 0.476, above the generic BP4 supporting cutoff of 0.29.	revel
BP5	Not assessed	Not assessed: somatic reports of p.Asp868Asn do not establish an alternate molecular basis for this patient's disease.	PMID:23222956 PMID:23832012 cosmic
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present; available submissions are Pathogenic or non-expert.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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