SETD5

protein-coding

SET domain containing 5, the group of SET domain containing

Gene summary

This function of this gene has yet to be determined but based on sequence similarity to other SET domain proteins it may function as a histone methyltransferase. Mutations in this gene have been associated with an autosomal dominant form of intellectual disability. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2017]

MANE transcript

NM_001080517.3

Inheritance

ClinVar variants

P:309U:598B:370

Top phenotype

Intellectual developmental disorder, autosomal dominant 23

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr3:9,397,615-9,479,240

External References & Databases

Ensembl (ENSG00000168137)

Transcript & Mutation Effects

hg38 • Region Span ~81.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiencySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014336

Submitter: PanelApp Australia

intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiencySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014336

Submitter: Labcorp Genetics (formerly Invitae)

intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiencyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014336

Submitter: G2P

syndromic complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0800439

Submitter: ClinGen

*SETD5* was first reported in relation to autosomal dominant syndromic complex neurodevelopmental disorder in 2013 (PMID: 24680889). Phenotypic features often reported in probands include: dysmorphic features, leg length discrepancies, feeding difficulties, developmental delays, autism, skeletal anomalies, and congenital malformations of various organ systems. This curation includes 19 variants (frameshift, deletions, missense, splice site) reported probands with phenotypic similarity (PMIDs: 28881385, 028120103, 28263952, 26482601, 29158550, 27375234, 32793091, 31656537, 29805509, 24680889, 25138099, 28549204). More evidence is available in the literature but the maximum score for genetic evidence (12 points) has been reached. Of note, three individuals with variants in *SETD5* and a distinct phenotype consistent with Moya Moya Disease, a rare, progressive cerebrovascular disorder caused by blocked arteries in the basal ganglia have also been reported, however that association has not been confirmed or reported again (PMID: 31474762). These individuals with Moya Moya did not have any neurodevelopmental delays and therefore were not scored in this curation. The mechanism of pathogenicity appears to be loss-of-function. In summary, there is definitive evidence supporting the relationship between *SETD5* and autosomal dominant syndromic complex neurodevelopmental disorder. This has been repeatedly demonstrated in the clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on the meeting date July 27, 2023 (SOP Version 9).

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 23AD

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: 24680889

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SETD5 variants in ClinVar

31 Conditions Cataloged

not providedTotal: 1100

Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiencyTotal: 256

Inborn genetic diseasesTotal: 224

SETD5-related disorderTotal: 65

not specifiedTotal: 49

Intellectual disabilityTotal: 10

See casesTotal: 8

Neurodevelopmental disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001080517.3. 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		2 clinvar	12 clinvar	184 clinvar	22 clinvar	220
missense	8 clinvar	29 clinvar	559 clinvar	156 clinvar	6 clinvar	758
nonsense	52 clinvar	25 clinvar	5 clinvar	1 clinvar		83
start loss						0
frameshift	116 clinvar	45 clinvar	13 clinvar	1 clinvar		175
splice donor/acceptor (+/-2bp)	14 clinvar	18 clinvar	9 clinvar			41
Total	190	119	598	342	28	1277

Highest pathogenic variant AF is 0.000006369896

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 93 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001080517.3	RefSeq	NP_001073986.1	21	MANE Select
ENST00000402198.7	Ensembl	ENSP00000385852.2	21	MANE Select
NM_001292043.2	RefSeq	NP_001278972.1	19	Standard
NM_001349451.2	RefSeq	NP_001336380.1	19	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
setd5	Danio rerio	Structure: head Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

setd5

Danio rerio

Structure: head

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Histone Modifications

Biological Process

covalent chromatin modification
regulation of histone acetylation
regulation of chromatin organization

Cellular Component

nucleus
nucleoplasm
Cdc73/Paf1 complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000402198
Coding exons: 21
Length: 81626
Individuals with no LoFs: 124610
Homozygous LoFs: 0
Heterozygous LoFs: 32
Defined: 124642
p: 0.000128

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.13	683	772	0.885	0.0000430	9258
Missense (PolyPhen)		177	311.9	0.56748		3567
Synonymous	-0.684	296	281	1.05	0.0000144	2959
Loss of Function	6.70	9	69.1	0.130	0.00000434	803

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0010	0.0010	notable
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0.00013	0.00013	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable transcriptional regulator that acts via the formation of large multiprotein complexes that modify and/or remodel the chromatin. Acts as a regulator of histone acetylation during gene transcription. {ECO:0000250|UniProtKB:Q5XJV7}.;
Disease: DISEASE: Mental retardation, autosomal dominant 23 (MRD23) [MIM:615761]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD23 patients manifest moderate to severe intellectual disability with additional variable features of brachycephaly, a low hairline, depressed nasal bridge, prominent high nasal root, tubular nose, upslanting palpebral fissures, long and smooth philtrum, micrognathia, thin upper lip, and crowded teeth. Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, are prominent features. {ECO:0000269|PubMed:24680889, ECO:0000269|PubMed:25138099, ECO:0000269|PubMed:27375234, ECO:0000269|PubMed:28549204}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.107

Intolerance Scores

LoFtool: 0.0174
RVIS EVS: -0.79
RVIS percentile EVS: 12.6

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.797

Gene Damage Prediction

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