SET

protein-coding

SET nuclear proto-oncogene, the group of SET complex|INHAT complex

Gene summary

The protein encoded by this gene inhibits acetylation of nucleosomes, especially histone H4, by histone acetylases (HAT). This inhibition is most likely accomplished by masking histone lysines from being acetylated, and the consequence is to silence HAT-dependent transcription. The encoded protein is part of a complex localized to the endoplasmic reticulum but is found in the nucleus and inhibits apoptosis following attack by cytotoxic T lymphocytes. This protein can also enhance DNA replication of the adenovirus genome. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

MANE transcript

NM_003011.4

Inheritance

ClinVar variants

P:40U:55B:17

Top phenotype

Intellectual developmental disorder, autosomal dominant 58

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr9:128,683,424-128,696,400

External References & Databases

Ensembl (ENSG00000119335)

Transcript & Mutation Effects

hg38 • Region Span ~13.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal dominant 58DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020847

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal dominant 58STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020847

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal dominant 58STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020847

Submitter: G2P

intellectual developmental disorder, autosomal dominant 58STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020847

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015802

Submitter: Orphanet

intellectual disabilityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0001071

Submitter: ClinGen

*SET* encodes a multifunctional protein involved in transcriptional regulation and chromatin remodeling. The relationship between variants in *SET* and autosomal dominant intellectual disability (ID) was first reported in 2018 (Stevens et al., PMID: 29688601; Richardson et al., PMID: 29907757). At least 9 variants (5 frameshift, 1 nonsense, 1 splice, 2 missense) have been reported in 10 individuals, with the majority occurring *de novo* (PMIDs: 25356899, 29688601, 29907757). Affected individuals presented with motor and speech delay, ID and variable additional features, including mild dysmorphic features, microcephaly in two individuals, and autism in one. The gene-disease relationship is further supported by experimental evidence, including interactions with proteins involved in histone modification and encoded by known autosomal dominant ID genes (e.g., *CREBBP, CTCF, EP300, KMT2A, SETBP1, RAC1, TREX1*) (PMID:29749127), and *in vitro* studies indicating *SET* is required for neuronal development (PMIDs: 20800572, 28966118). In summary, *SET* is definitively associated with autosomal dominant intellectual disability. This was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 17, 2021 (SOP version 8).

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 58AD

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 28135719; 28135719; 29688601

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SET variants in ClinVar

10 Conditions Cataloged

not providedTotal: 59

Intellectual disability, autosomal dominant 58Total: 49

Inborn genetic diseasesTotal: 15

SET-related disorderTotal: 13

not specifiedTotal: 7

DysgerminomaTotal: 1

Global developmental delayTotal: 1

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003011.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				12 clinvar		12
missense		5 clinvar	45 clinvar	4 clinvar		54
nonsense	4 clinvar	1 clinvar				5
start loss	1 clinvar					1
frameshift	13 clinvar	12 clinvar	4 clinvar	1 clinvar		30
splice donor/acceptor (+/-2bp)	3 clinvar	1 clinvar	6 clinvar			10
Total	21	19	55	17	0	112

Highest pathogenic variant AF is 0.000002575284

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003011.4	RefSeq	NP_003002.2	8	MANE Select
ENST00000322030.13	Ensembl	ENSP00000318012.9	8	MANE Select
NM_001122821.2	RefSeq	NP_001116293.1	8	Standard
NM_001248000.2	RefSeq	NP_001234929.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
setb	Danio rerio	Structure: post-vent region Quality: curved abnormal

Gene / Model

Organism

Observed Phenotype

setb

Danio rerio

Structure: post-vent region

Quality: curved

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

NOTCH-Ncore
Histone Modifications
granzyme a mediated apoptosis pathway
Metabolism of RNA
HuR (ELAVL1) binds and stabilizes mRNA

Biological Process

DNA replication
nucleosome assembly
nucleosome disassembly
viral process
negative regulation of phosphoprotein phosphatase activity

Molecular Function

DNA binding
protein phosphatase inhibitor activity
protein binding
protein phosphatase regulator activity
histone binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
endoplasmic reticulum
lipid droplet

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000372692
Coding exons: 8
Length: 12977
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.66	55	145	0.379	0.00000706	1935
Missense (PolyPhen)		1	25.35	0.039448		446
Synonymous	-0.598	60	54.4	1.10	0.00000304	471
Loss of Function	3.74	0	16.3	0.00	6.88e-7	220

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Multitasking protein, involved in apoptosis, transcription, nucleosome assembly and histone chaperoning. Isoform 2 anti-apoptotic activity is mediated by inhibition of the GZMA-activated DNase, NME1. In the course of cytotoxic T- lymphocyte (CTL)-induced apoptosis, GZMA cleaves SET, disrupting its binding to NME1 and releasing NME1 inhibition. Isoform 1 and isoform 2 are potent inhibitors of protein phosphatase 2A. Isoform 1 and isoform 2 inhibit EP300/CREBBP and PCAF-mediated acetylation of histones (HAT) and nucleosomes, most probably by masking the accessibility of lysines of histones to the acetylases. The predominant target for inhibition is histone H4. HAT inhibition leads to silencing of HAT-dependent transcription and prevents active demethylation of DNA. Both isoforms stimulate DNA replication of the adenovirus genome complexed with viral core proteins; however, isoform 2 specific activity is higher. {ECO:0000269|PubMed:11555662, ECO:0000269|PubMed:12628186}.;
Disease: DISEASE: Note=A chromosomal aberration involving SET is found in some cases of acute undifferentiated leukemia (AUL). Translocation t(6;9)(q21;q34.1) with NUP214/CAN.;

Recessive Scores

pRec: 0.296

Intolerance Scores

LoFtool: 0.435
RVIS EVS: 0.3
RVIS percentile EVS: 72.01

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.993

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium