SETD5

Summary

SETD5 (SET domain containing 5, HGNC:25566) is a protein-coding gene on chromosome 3p25.3, encoding Histone-lysine N-methyltransferase SETD5 (Q9C0A6). Chromatin regulator required for brain development: acts as a regulator of RNA elongation rate, thereby regulating neural stem cell (NSC) proliferation and synaptic transmission. It is a selective cancer dependency (DepMap: 17.2% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

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.

Source: NCBI Gene 55209 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 1,461 total — 180 pathogenic, 87 likely-pathogenic
• Phenotypes (HPO): 79
• Cancer dependency (DepMap): dependent in 17.2% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001080517

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25566
Approved symbol	SETD5
Name	SET domain containing 5
Location	3p25.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10707, SETD5A
Ensembl gene	ENSG00000168137
Ensembl biotype	protein_coding
OMIM	615743
Entrez	55209

Gene structure

Transcript identifiers

Ensembl transcripts: 47 — 18 retained_intron, 13 protein_coding, 13 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000399686, ENST00000402198, ENST00000406341, ENST00000407969, ENST00000413704, ENST00000415650, ENST00000421188, ENST00000431285, ENST00000443339, ENST00000459941, ENST00000463180, ENST00000466242, ENST00000466826, ENST00000468208, ENST00000476740, ENST00000478475, ENST00000478961, ENST00000479538, ENST00000486465, ENST00000488236, ENST00000490791, ENST00000492939, ENST00000493918, ENST00000497213, ENST00000663774, ENST00000665872, ENST00000666307, ENST00000670063, ENST00000682236, ENST00000682536, ENST00000683012, ENST00000683262, ENST00000684055, ENST00000684606, ENST00000687014, ENST00000688835, ENST00000689167, ENST00000691175, ENST00000691299, ENST00000691659, ENST00000691925, ENST00000691988, ENST00000692920, ENST00000693430, ENST00000866905, ENST00000866906, ENST00000866907

RefSeq mRNA: 3 — MANE Select: NM_001080517 NM_001080517, NM_001292043, NM_001349451

CCDS: CCDS46741

Canonical transcript exons

ENST00000402198 — 23 exons

Exon	Start	End
ENSE00001556197	9424467	9424526
ENSE00003462048	9443308	9443417
ENSE00003478442	9434334	9434485
ENSE00003484516	9445048	9445300
ENSE00003493230	9470459	9470929
ENSE00003531309	9464425	9464672
ENSE00003563854	9428823	9429009
ENSE00003570043	9440456	9440698
ENSE00003584358	9435728	9435906
ENSE00003584678	9441593	9441741
ENSE00003586004	9474449	9474582
ENSE00003596425	9433845	9433950
ENSE00003596653	9475068	9475156
ENSE00003614115	9473236	9473537
ENSE00003617260	9453739	9453868
ENSE00003631539	9445657	9445740
ENSE00003653933	9447686	9448006
ENSE00003663407	9447050	9447307
ENSE00003680712	9448388	9448630
ENSE00003688137	9434824	9434882
ENSE00003689203	9442128	9442245
ENSE00003899192	9475483	9478154
ENSE00003902562	9397615	9397977

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 98.40.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.1911 / max 358.4458, expressed in 1816 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
35205	26.8421	1810
35209	10.0068	1771
35208	1.8051	1102
35210	1.3695	775
35215	0.1065	38
35212	0.0611	29

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	98.40	gold quality
colonic epithelium	UBERON:0000397	97.86	gold quality
sural nerve	UBERON:0015488	97.64	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.58	gold quality
cerebellar hemisphere	UBERON:0002245	97.43	gold quality
cerebellar cortex	UBERON:0002129	97.39	gold quality
right uterine tube	UBERON:0001302	97.18	gold quality
cerebellum	UBERON:0002037	97.16	gold quality
right lobe of thyroid gland	UBERON:0001119	97.11	gold quality
ventricular zone	UBERON:0003053	97.04	gold quality
body of uterus	UBERON:0009853	97.00	gold quality
left lobe of thyroid gland	UBERON:0001120	96.96	gold quality
mucosa of stomach	UBERON:0001199	96.87	gold quality
left ovary	UBERON:0002119	96.82	gold quality
thyroid gland	UBERON:0002046	96.77	gold quality
calcaneal tendon	UBERON:0003701	96.75	gold quality
right ovary	UBERON:0002118	96.69	gold quality
endocervix	UBERON:0000458	96.53	gold quality
tibial nerve	UBERON:0001323	96.41	gold quality
minor salivary gland	UBERON:0001830	96.39	gold quality
ectocervix	UBERON:0012249	96.29	gold quality
body of pancreas	UBERON:0001150	96.27	gold quality
skin of leg	UBERON:0001511	96.26	gold quality
vagina	UBERON:0000996	96.21	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.19	gold quality
right adrenal gland cortex	UBERON:0035827	96.19	gold quality
skin of abdomen	UBERON:0001416	96.11	gold quality
upper lobe of left lung	UBERON:0008952	96.08	gold quality
right lung	UBERON:0002167	96.06	gold quality
upper leg skin	UBERON:0004262	96.03	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.08
E-GEOD-137537	yes	6.52

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

217 targeting SETD5, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 17.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 16)

• miR126-5p is a functional, endothelial-enriched microRNA that participates in the control of leucocyte trafficking by regulating the expression of ALCAM and SetD5. (PMID:24562769)
• analysis provides sufficient evidence that rare de novo LoF mutations in SETD5 are a relatively frequent (0.7%) cause of intellectual disability (PMID:24680889)
• SETD5 sequence variants contribute substantially to the microdeletion 3p25.3 phenotype. SETD5 variants as a relatively frequent cause of intellectual disability. (PMID:25138099)
• We present the first familial case of a SETD5 mutation contributing to a phenotype of congenital heart defects and dysmorphic features, with variable expression, in two siblings and their father. Interestingly, the father demonstrated only mild intellectual impairment. (PMID:27375234)
• SETD5 frameshift mutation identified in a patient with mild intellectual disability. (PMID:28549204)
• We suggest that the phenotype of SETD5 is more complex and variable than previously presented. Therefore, many features and presentations need to be considered when evaluating a patient for SETD5 alterations through Diagnostic exome sequencing . (PMID:28881385)
• Review mapped the clinical phenotypes of 42 individuals carrying mutations on the SETD5 gene, with 23.8% presenting autistic-like features. Most of mutations occurred between positions 9,480,000-9,500,000 bp on chromosome 3 (3p25.3) at the SETD5 gene locus. In all males, mutations in SETD5 presented high penetrance, while in females the clinical phenotype seems more variable. (PMID:29484850)
• These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes. Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified (PMID:30190612)
• Study results suggest that SETD5 could regulate p-P90RSK and facilitate the migration and invasion of non-small cell lung cancer (NSCLC) and may be related to the poor prognosis of patients with NSCLC. (PMID:31345185)
• The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy. (PMID:31474762)
• SET domain-containing 5 is a potential prognostic biomarker that promotes esophageal squamous cell carcinoma stemness. (PMID:31981592)
• Su(var)3-9, Enhancer of Zeste, and Trithorax Domain-Containing 5 Facilitates Tumor Growth and Pulmonary Metastasis through Up-Regulation of AKT1 Signaling in Breast Cancer. (PMID:33129761)
• SET Domain-Containing Protein 5 Enhances the Cell Stemness of Non-Small Cell Lung Cancer via the PI3K/Akt/mTOR Pathway. (PMID:33822517)
• SETD5 Regulates Glycolysis in Breast Cancer Stem-Like Cells and Fuels Tumor Growth. (PMID:35063407)
• Structure, activity and function of the lysine methyltransferase SETD5. (PMID:36875494)
• SETD5 haploinsufficiency affects mitochondrial compartment in neural cells. (PMID:37264456)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	setd5	ENSDARG00000078576
mus_musculus	Setd5	ENSMUSG00000034269
rattus_norvegicus	Setd5	ENSRNOG00000007472
drosophila_melanogaster	upSET	FBGN0036398
caenorhabditis_elegans		WBGENE00012845
caenorhabditis_elegans		WBGENE00013106
caenorhabditis_elegans		WBGENE00017482

Paralogs (1): KMT2E (ENSG00000005483)

Protein

Protein identifiers

Histone-lysine N-methyltransferase SETD5 — Q9C0A6 (reviewed: Q9C0A6)

Alternative names: SET domain-containing protein 5

All UniProt accessions (13): A0A804HI68, A0A804HI72, A0A804HJ18, A0A804HK73, Q9C0A6, A0A804HKJ6, A0A804HKJ9, E7EWN3, F2Z2J0, F8WD12, H0Y3R4, H7C1F2, H7C1Q2

UniProt curated annotations — full annotation on UniProt →

Function. Chromatin regulator required for brain development: acts as a regulator of RNA elongation rate, thereby regulating neural stem cell (NSC) proliferation and synaptic transmission. May act by mediating trimethylation of ‘Lys-36’ of histone H3 (H3K36me3), which is essential to allow on-time RNA elongation dynamics. Also monomethylates ‘Lys-9’ of histone H3 (H3K9me1) in vitro. The relevance of histone methyltransferase activity is however subject to discussion.

Subunit / interactions. Interacts with components of the PAF1 complex (PAF1C) such as LEO1, CTR9 and CDC73. Interacts with NCOR1. Interacts with HDAC3.

Subcellular location. Nucleus. Chromosome.

Disease relevance. Intellectual developmental disorder, 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. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9C0A6-1	1	yes
Q9C0A6-2	2
Q9C0A6-3	3

RefSeq proteins (3): NP_001073986, NP_001278972, NP_001336380 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001214	SET_dom	Domain
IPR044433	SETD5_SET	Domain
IPR046341	SET_dom_sf	Homologous_superfamily

Pfam: PF00856

Catalyzed reactions (Rhea), 2 shown:

• L-lysyl(9)-[histone H3] + S-adenosyl-L-methionine = N(6)-methyl-L-lysyl(9)-[histone H3] + S-adenosyl-L-homocysteine + H(+) (RHEA:60280)
• L-lysyl(36)-[histone H3] + 3 S-adenosyl-L-methionine = N(6),N(6),N(6)-trimethyl-L-lysyl(36)-[histone H3] + 3 S-adenosyl-L-homocysteine + 3 H(+) (RHEA:60324)

UniProt features (56 total): compositionally biased region 21, sequence variant 14, region of interest 8, modified residue 5, sequence conflict 4, splice variant 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9C0A6-F1	47.10	0.08

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (5): 72, 829, 852, 855, 1198

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 427 (showing top): GOBP_COGNITION, GOBP_SYNAPSE_ASSEMBLY, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_TRANSCRIPTION_BY_RNA_POLYMERASE_III, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_REGULATION_OF_SYNAPSE_ASSEMBLY, GOBP_REGULATION_OF_SYNAPSE_STRUCTURE_OR_ACTIVITY, GOBP_REGULATION_OF_CHROMATIN_ORGANIZATION, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, HOEBEKE_LYMPHOID_STEM_CELL_UP, GOBP_CELL_JUNCTION_ASSEMBLY, SENESE_HDAC1_TARGETS_UP, GOBP_CHROMATIN_REMODELING

GO Biological Process (9): regulation of DNA-templated transcription (GO:0006355), negative regulation of transcription by RNA polymerase III (GO:0016480), methylation (GO:0032259), regulation of DNA-templated transcription elongation (GO:0032784), cognition (GO:0050890), regulation of synapse assembly (GO:0051963), regulation of chromatin organization (GO:1902275), chromatin organization (GO:0006325), chromatin remodeling (GO:0006338)

GO Molecular Function (9): transcription corepressor activity (GO:0003714), histone H3K9 methyltransferase activity (GO:0046974), histone H3K36 methyltransferase activity (GO:0046975), histone H3K9 monomethyltransferase activity (GO:0140948), histone H3K36 trimethyltransferase activity (GO:0140955), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740), histone H3K9me2 methyltransferase activity (GO:0140947)

GO Cellular Component (7): chromatin (GO:0000785), euchromatin (GO:0000791), nucleus (GO:0005634), nucleoplasm (GO:0005654), Set3 complex (GO:0034967), Rpd3L-Expanded complex (GO:0070210), chromosome (GO:0005694)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
chromatin	3
negative regulation of DNA-templated transcription	2
chromatin organization	2
protein-lysine N-methyltransferase activity	2
histone H3 methyltransferase activity	2
histone H3K9 methyltransferase activity	2
cellular anatomical structure	2
histone deacetylase complex	2
nuclear chromosome	2
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase III	1
transcription by RNA polymerase III	1
metabolic process	1
DNA-templated transcription elongation	1
regulation of DNA-templated transcription	1
nervous system process	1
synapse assembly	1
regulation of synapse organization	1
regulation of cell junction assembly	1
regulation of cellular component organization	1
cellular component organization	1
transcription coregulator activity	1
histone H3K36 methyltransferase activity	1
binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1752 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SETD5	THUMPD3	Q9BV44	717
SETD5	ANKRD11	Q6UB99	578
SETD5	SETD4	Q9NVD3	568
SETD5	KMT5B	Q4FZB7	513
SETD5	SETD3	Q86TU7	498
SETD5	LHFPL4	Q7Z7J7	492
SETD5	CHD8	Q9HCK8	476
SETD5	SETD7	Q8WTS6	468
SETD5	SETMAR	Q53H47	464
SETD5	CCDC106	Q9BWC9	456
SETD5	RSPRY1	Q96DX4	455
SETD5	MOSMO	Q8NHV5	454
SETD5	SMYD3	Q9H7B4	453
SETD5	BTBD8	Q5XKL5	443
SETD5	SETD6	Q8TBK2	442

IntAct

29 interactions, top by confidence:

A	B	Type	Score
NAGK	ZBTB43	psi-mi:“MI:0914”(association)	0.530
PRR20E	SIAH2	psi-mi:“MI:0914”(association)	0.530
RMND5B	PSMA7	psi-mi:“MI:0914”(association)	0.510
USP20	SETD5	psi-mi:“MI:0915”(physical association)	0.500
SETD5	LDOC1	psi-mi:“MI:0915”(physical association)	0.490
MTUS2	SETD5	psi-mi:“MI:0915”(physical association)	0.370
SETD5	DPPA2	psi-mi:“MI:0915”(physical association)	0.370
CCDC85B	SETD5	psi-mi:“MI:0915”(physical association)	0.370
TRAF2	SETD5	psi-mi:“MI:0915”(physical association)	0.370
SPAG16	ADCY6	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
PRMT2	KRBA1	psi-mi:“MI:0914”(association)	0.350
SKAP1	MYO9A	psi-mi:“MI:0914”(association)	0.350
PRR20E	ZNF593	psi-mi:“MI:0914”(association)	0.350
SSRP1	DDX39A	psi-mi:“MI:0914”(association)	0.350
PIPSL	C1orf226	psi-mi:“MI:0914”(association)	0.350
FTL	SH3PXD2B	psi-mi:“MI:0914”(association)	0.350
FBLN5	ZNF320	psi-mi:“MI:0914”(association)	0.350
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350
USP20	MYO9A	psi-mi:“MI:0914”(association)	0.350
SPAG16	SETD5	psi-mi:“MI:0915”(physical association)	0.000
RMND5B	SETD5	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (84): SETD5 (Two-hybrid), CEP70 (Two-hybrid), KRT40 (Two-hybrid), SETD5 (Affinity Capture-RNA), SETD5 (Affinity Capture-MS), SETD5 (Affinity Capture-MS), DPPA2 (Two-hybrid), SETD5 (Two-hybrid), SETD5 (Two-hybrid), SETD5 (Affinity Capture-MS), SETD5 (Affinity Capture-MS), SETD5 (Affinity Capture-MS), SETD5 (Affinity Capture-MS), SETD5 (Affinity Capture-MS), SETD5 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8GR68, A2CG63, E9Q9M8, F7AQ22, G3V8T1, O75152, O75376, P49140, P51826, P97432, Q13625, Q14596, Q17R98, Q1LY51, Q3TYA6, Q4KKX4, Q4LE39, Q4R6F6, Q501R9, Q505G8, Q5F3Z9, Q5HYC2, Q5RC94, Q5XJV7, Q60974, Q68FE8, Q69Z61, Q6A098, Q6NXK2, Q6NZF1, Q6PJT7, Q6ZNC4, Q86YI8, Q8BFU3, Q8BJ05, Q8CCH7, Q8CG79, Q8CHY6, Q8K2W6, Q8ND24

Diamond homologs: A6ZZW1, A8MW92, O44498, P36106, Q08923, Q10362, Q4V9H5, Q5XJV7, Q8CCJ9, Q9C0A6, Q9NR48, Q9U263, Q9Y7V2, P36124, Q1MTR4, Q2LAE1, Q3UG20, Q7X6Y7, Q8BLG0, Q8IZD2, Q945S8, Q99MY8, Q9BVI0, Q9FMS5, Q9M1X9, Q9VW15, Q9VYD1

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
SETD5	up-regulates	Epigenetic_regulation
SETD5	“up-regulates activity”	H3C1	methylation
SETD5	“up-regulates activity”	H3-4	methylation
SETD5	“up-regulates activity”	H3-3A	methylation
SETD5	“up-regulates activity”	“Histone H3”	methylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

1461 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	180
Likely pathogenic	87
Uncertain significance	612
Likely benign	353
Benign	66

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1032602	NM_001080517.3(SETD5):c.1390C>T (p.Gln464Ter)	Pathogenic
1032603	NM_001080517.3(SETD5):c.1495del (p.Asp499fs)	Pathogenic
1070036	NM_001080517.3(SETD5):c.2965_2972dup (p.Asn991_Ala992insLeuTer)	Pathogenic
1073863	NM_001080517.3(SETD5):c.2983C>T (p.Arg995Ter)	Pathogenic
1075967	NM_001080517.3(SETD5):c.3038del (p.His1013fs)	Pathogenic
1075980	NM_001080517.3(SETD5):c.3631+1G>A	Pathogenic
1119984	NM_001080517.3(SETD5):c.2343_2344delinsTT (p.Lys781_Lys782delinsAsnTer)	Pathogenic
1172660	NM_001080517.1:r.627_810del	Pathogenic
1183999	NM_001080517.3(SETD5):c.759_760del (p.Ile253_Asn254insTer)	Pathogenic
1220311	NM_001080517.3(SETD5):c.1248del (p.Asn417fs)	Pathogenic
127102	NM_001080517.3(SETD5):c.1195A>T (p.Lys399Ter)	Pathogenic
127103	NM_001080517.3(SETD5):c.2177_2178del (p.Thr726fs)	Pathogenic
127104	NM_001080517.3(SETD5):c.3001C>T (p.Arg1001Ter)	Pathogenic
127105	NM_001080517.3(SETD5):c.3771dup (p.Ser1258fs)	Pathogenic
1301864	NM_001080517.3(SETD5):c.2182del (p.Asp728fs)	Pathogenic
1321988	NM_001080517.3(SETD5):c.536del (p.Gly179fs)	Pathogenic
1323579	NM_001080517.3(SETD5):c.889_890del (p.Leu297fs)	Pathogenic
1325818	NM_001080517.3(SETD5):c.1689del (p.Glu564fs)	Pathogenic
1343149	NM_001080517.3(SETD5):c.890_897delinsC (p.Leu297fs)	Pathogenic
1343278	NM_001080517.3(SETD5):c.1028dup (p.Gly344fs)	Pathogenic
1451659	NM_001080517.3(SETD5):c.1525-1G>A	Pathogenic
1458566	NM_001080517.3(SETD5):c.3301C>T (p.Gln1101Ter)	Pathogenic
1459443	NC_000003.11:g.(?9470623)(9485121_?)del	Pathogenic
1459974	NC_000003.11:g.(?9506089)(9506376_?)del	Pathogenic
1476332	NM_001080517.3(SETD5):c.960-6C>G	Pathogenic
1527877	NM_001080517.3(SETD5):c.489dup (p.Val164fs)	Pathogenic
1677815	NM_001080517.3(SETD5):c.829dup (p.Thr277fs)	Pathogenic
1678815	NM_001080517.3(SETD5):c.2881A>T (p.Arg961Ter)	Pathogenic
1679232	NM_001080517.3(SETD5):c.1967del (p.Ser655_Leu656insTer)	Pathogenic
1679238	NM_001080517.3(SETD5):c.1612C>T (p.Gln538Ter)	Pathogenic

SpliceAI

5412 predictions. Top by Δscore:

Variant	Effect	Δscore
3:9413605:G:GT	donor_gain	1.0000
3:9428820:CAGG:C	acceptor_loss	1.0000
3:9428821:A:AG	acceptor_gain	1.0000
3:9428821:AG:A	acceptor_gain	1.0000
3:9428822:G:A	acceptor_loss	1.0000
3:9428822:G:GG	acceptor_gain	1.0000
3:9428822:GG:G	acceptor_gain	1.0000
3:9428822:GGATT:G	acceptor_gain	1.0000
3:9429005:TCAGA:T	donor_gain	1.0000
3:9429008:GA:G	donor_gain	1.0000
3:9429009:AG:A	donor_loss	1.0000
3:9429010:G:A	donor_loss	1.0000
3:9429010:G:GG	donor_gain	1.0000
3:9429012:AAGT:A	donor_loss	1.0000
3:9433839:GTGCA:G	acceptor_loss	1.0000
3:9433841:GCAG:G	acceptor_loss	1.0000
3:9433842:CAGCC:C	acceptor_loss	1.0000
3:9433843:A:AG	acceptor_gain	1.0000
3:9433843:A:T	acceptor_loss	1.0000
3:9433844:G:GA	acceptor_gain	1.0000
3:9433844:GC:G	acceptor_gain	1.0000
3:9433844:GCC:G	acceptor_gain	1.0000
3:9433844:GCCC:G	acceptor_gain	1.0000
3:9433844:GCCCT:G	acceptor_gain	1.0000
3:9433948:GCT:G	donor_gain	1.0000
3:9433951:G:GG	donor_gain	1.0000
3:9434275:A:AG	acceptor_gain	1.0000
3:9434276:G:GG	acceptor_gain	1.0000
3:9434482:GCAG:G	donor_gain	1.0000
3:9434483:CAG:C	donor_gain	1.0000

AlphaMissense

9325 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:9435787:T:G	Y150D	1.000
3:9435818:T:A	I160N	1.000
3:9435818:T:G	I160S	1.000
3:9435824:T:C	L162S	1.000
3:9440504:T:A	W206R	1.000
3:9440504:T:C	W206R	1.000
3:9440506:G:C	W206C	1.000
3:9440506:G:T	W206C	1.000
3:9440525:T:A	W213R	1.000
3:9440525:T:C	W213R	1.000
3:9440527:G:C	W213C	1.000
3:9440527:G:T	W213C	1.000
3:9440557:T:A	N223K	1.000
3:9440557:T:G	N223K	1.000
3:9440561:T:G	Y225D	1.000
3:9440564:A:C	S226R	1.000
3:9440566:T:A	S226R	1.000
3:9440566:T:G	S226R	1.000
3:9441639:T:C	L286P	1.000
3:9441675:T:A	I298K	1.000
3:9441675:T:G	I298R	1.000
3:9441678:T:A	I299K	1.000
3:9441683:T:C	Y301H	1.000
3:9441683:T:G	Y301D	1.000
3:9441687:G:C	R302P	1.000
3:9441689:G:A	G303R	1.000
3:9441689:G:C	G303R	1.000
3:9441689:G:T	G303W	1.000
3:9441690:G:A	G303E	1.000
3:9441690:G:T	G303V	1.000

dbSNP variants (sampled 300 via entrez): RS1000013678 (3:9438996 CAGTG>C), RS1000015198 (3:9477991 G>C,T), RS1000037942 (3:9398907 G>A), RS1000088506 (3:9478276 G>C), RS1000155713 (3:9432506 A>G,T), RS1000225565 (3:9396483 G>A,C,T), RS1000248153 (3:9415850 A>C), RS1000265162 (3:9426262 G>A,C), RS1000314882 (3:9429563 T>G), RS1000362303 (3:9466424 GGTTTTGTTTT>G,GGTTTT,GGTTTTGTTTTGTTTT), RS1000367744 (3:9418398 A>C), RS1000419484 (3:9423490 A>G), RS1000453578 (3:9423642 C>A,G), RS1000461938 (3:9420261 TA>T), RS1000468731 (3:9464173 G>A)

Disease associations

OMIM: gene MIM:615743 | disease phenotypes: MIM:615761, MIM:617600, MIM:615716, MIM:148050

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
syndromic complex neurodevelopmental disorder	Definitive	AD

Mondo (15): intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (MONDO:0014336), intellectual disability (MONDO:0001071), intellectual disability, autosomal dominant 45 (MONDO:0030910), hearing loss disorder (MONDO:0005365), neurodevelopmental disorder (MONDO:0700092), syndromic intellectual disability (MONDO:0000508), non-syndromic intellectual disability (MONDO:0000509), hyperphosphatasia with intellectual disability syndrome 4 (MONDO:0014318), NK-cell enteropathy (MONDO:0016996), microcephaly (MONDO:0001149), polymicrogyria (MONDO:0000087), autism spectrum disorder (MONDO:0005258), cleft lip (MONDO:0004747), cleft palate (MONDO:0016064), KBG syndrome (MONDO:0007846)

Orphanet (10): OBSOLETE: Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (Orphanet:404440), Rare genetic syndromic intellectual disability (Orphanet:183763), Hyperphosphatasia-intellectual disability syndrome (Orphanet:247262), NK-cell enteropathy (Orphanet:263665), Polymicrogyria (Orphanet:35981), Rare genetic intellectual disability (Orphanet:183757), Cleft palate (Orphanet:2014), KBG syndrome (Orphanet:2332), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

79 total (30 of 79 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000047	Hypospadias
HP:0000175	Cleft palate
HP:0000219	Thin upper lip vermilion
HP:0000248	Brachycephaly
HP:0000286	Epicanthus
HP:0000294	Low anterior hairline
HP:0000303	Mandibular prognathia
HP:0000319	Smooth philtrum
HP:0000322	Short philtrum
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000356	Abnormality of the outer ear
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000414	Bulbous nose
HP:0000431	Wide nasal bridge
HP:0000448	Prominent nose
HP:0000463	Anteverted nares
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000545	Myopia
HP:0000568	Microphthalmia
HP:0000581	Blepharophimosis
HP:0000582	Upslanted palpebral fissure
HP:0000664	Synophrys

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002726_11	Glucose homeostasis traits	3.000000e-06
GCST003134_19	Cerebrospinal fluid clusterin levels	8.000000e-06
GCST008522_79	Bitter alcoholic beverage consumption	5.000000e-06
GCST010221_1	Attention deficit hyperactivity disorder (inattention symptoms)	3.000000e-06
GCST010988_131	Adult body size	1.000000e-09
GCST011122_40	Walking pace	4.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004471	insulin sensitivity measurement
EFO:0010092	bitter alcoholic beverage consumption measurement

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D002971	Cleft Lip	C07.465.409.225; C07.465.525.164; C07.650.525.164; C16.131.850.525.164
D002972	Cleft Palate	C05.500.460.185; C05.660.207.540.460.185; C07.320.440.185; C07.465.525.185; C07.650.500.460.185; C07.650.525.185; C16.131.621.207.540.460.185; C16.131.850.500.460.185; C16.131.850.525.185
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D065886	Neurodevelopmental Disorders	F03.625
D065706	Polymicrogyria	C10.500.507.500.500; C16.131.666.507.500.500
C537015	KBG syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

55 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation	5
bisphenol A	increases expression, affects cotreatment, increases methylation, decreases expression	3
trichostatin A	affects cotreatment, increases expression	3
Benzo(a)pyrene	decreases expression	3
Cyclosporine	increases expression, increases methylation	2
Cadmium Chloride	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
bufotalin	decreases expression	1
methylmercuric chloride	increases expression	1
salinomycin	decreases expression	1
methylparaben	increases expression	1
sodium arsenite	increases expression	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CD 437	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	increases expression	1
abrine	increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
bisphenol S	affects cotreatment, decreases expression	1
Irinotecan	decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Vehicle Emissions	increases abundance, increases expression	1
Benzene	increases expression	1
Berberine	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_DX06	HAP1 SETD5 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children