SETBP1

Chr 18

SET binding protein 1

Also known as: MRD29, SEB

NCBI Gene: 26040 ENSG00000152217 UniProt: Q9Y6X0

The protein binds the SET nuclear oncogene and regulates DNA replication through its SET-binding region and ski homology domain. Mutations cause Schinzel-Giedion midface retraction syndrome and autosomal dominant intellectual developmental disorder through loss-of-function mechanisms. The inheritance pattern is autosomal dominant with extremely high intolerance to loss-of-function variants.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein which contains a several motifs including a ski homology region and a SET-binding region in addition to three nuclear localization signals. The encoded protein has been shown to bind the SET nuclear oncogene which is involved in DNA replication. Mutations in this gene are associated with Schinzel-Giedion midface retraction syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

GeneReviews ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.11

Clinical Summary— SETBP1

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

35 unique Pathogenic / Likely Pathogenic· 369 VUS of 687 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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GeneReview available — SETBP1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.11LOEUF

pLI 1.000

Z-score 5.95

OE 0.02 (0.01–0.11)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

1.10Z-score

OE missense 0.90 (0.84–0.95)

776 obs / 866.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.02 (0.01–0.11)

0≤0.351.4

Missense OE?0.90 (0.84–0.95)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 1 / 43.3Missense obs/exp: 776 / 866.8Syn Z: -1.06

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSETBP1-related developmental and expressive language delayLOFAD

definitiveSETBP1-related Schinzel-Giedion midface retraction syndromeGOFAD

This gene — mechanism propensity

0.2199th %ile

GOF

0.2597th %ile

LOF

0.90top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 86% of P/LP variants are LoF · LOEUF 0.11 · ClinGen HI: Sufficient evidence for dosage pathogenicity

GOF1 literature citation

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNAs rare 18q interstitial deletions affecting multiple genes including SETBP1 correlate with a milder phenotype, including minor physical anomalies and developmental and expressive speech delay, mutations in SETBP1 are thought to result in a gain-of-function or a dominant-negative effect.1

GOFThere is another indication that severity of phenotype of SGS may be inversely correlated with degree of SETBP1 alteration, besides gain-of-function or dominant-negative effects in SETBP1 alteration causing SGS.2

LOFClinical delineation of SETBP1 haploinsufficiency disorder.3

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

687 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic26

Likely Pathogenic9

VUS369

Likely Benign216

Benign51

Conflicting8

Pathogenic

Likely Pathogenic

369

VUS

216

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	23	2	1	0	26
Likely Pathogenic	7	1	1	0	9
VUS	3	351	15	0	369
Likely Benign	0	53	15	148	216
Benign	0	32	1	18	51
Conflicting	—				8
Total	33	439	33	166	679

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

11 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap SETBP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →