SETD1B

protein-coding

SET domain containing 1B, histone lysine methyltransferase, the group of Lysine methyltransferases|RNA binding motif containing|SET domain containing

Gene summary

SET1B is a component of a histone methyltransferase complex that produces trimethylated histone H3 at Lys4 (Lee et al., 2007 [PubMed 17355966]).[supplied by OMIM, Mar 2008]

MANE transcript

NM_001353345.2

Inheritance

ClinVar variants

P:117U:467B:288

Top phenotype

Intellectual developmental disorder with seizures and language delay

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr12:121,804,009-121,832,656

External References & Databases

Ensembl (ENSG00000139718)

Transcript & Mutation Effects

hg38 • Region Span ~28.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder with seizures and language delaySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033559

Submitter: PanelApp Australia

intellectual developmental disorder with seizures and language delaySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033559

Submitter: G2P

intellectual developmental disorder with seizures and language delaySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033559

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*SETD1B* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2018 (Hiraide et al., PMID: 29322246). Individuals with heterozygous variants in *SETD1B* have been reported to present with seizures, intellectual disability/developmental delay, speech delay, motor delay, autism, behavioral disorders, facial dysmorphism, and obesity. Six variants (frameshift, nonsense, splice) that have been reported in 6 probands in 4 publications (PMIDs: 34345025, 32546566, 31685013, 38048716) are included in this curation. Additional evidence (including missense variants with supportive functional data) has been reported in the literature (PMIDs: 35385430, 31440728, 29322246, 38313655, 38108116, 31110234), but the maximum for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. The autosomal dominant gene-disease relationship is also supported by experimental evidence including animal models (mouse, PMID: 34806773, drosophila melanogaster PMID: 32346159) and protein interaction experiments (PMID: 34806773). In summary, there is definitive evidence supporting the relationship between *SETD1B* and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen ID Autism GCEP on the meeting date 08/20/2024 (SOP Version 10). Of note, four individuals from three families with biallelic missense variants with similar neurodevelopmental phenotypes have also been reported, and are not included in this curation (PMID: 34345025). Additional information is needed to determine the role of biallelic variants in disease.

intellectual developmental disorder with seizures and language delayMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0033559

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Intellectual developmental disorder with seizures and language delayAD

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: 29322246; 31110234; 32546566

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SETD1B variants in ClinVar

15 Conditions Cataloged

not providedTotal: 399

Inborn genetic diseasesTotal: 243

not specifiedTotal: 208

Intellectual developmental disorder with seizures and language delayTotal: 173

SETD1B-related disorderTotal: 119

Neurodevelopmental disorderTotal: 4

See casesTotal: 3

Complex neurodevelopmental disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001353345.2. 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			4 clinvar	165 clinvar	4 clinvar	173
missense	11 clinvar	20 clinvar	454 clinvar	115 clinvar	4 clinvar	604
nonsense	17 clinvar	5 clinvar	1 clinvar			23
start loss						0
frameshift	31 clinvar	28 clinvar	4 clinvar			63
splice donor/acceptor (+/-2bp)	1 clinvar	4 clinvar	4 clinvar			9
Total	60	57	467	280	8	872

Highest pathogenic variant AF is 0.0005546786

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001353345.2	RefSeq	NP_001340274.1	16	MANE Select
ENST00000604567.6	Ensembl	ENSP00000474253.1	16	MANE Select
ENST00000542440.5	Ensembl	ENSP00000442924.1	17	Standard
ENST00000542440.6	Ensembl	ENSP00000442924.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysine degradation - Homo sapiens (human)
Histone Modifications
Gene expression (Transcription)
Generic Transcription Pathway
PKMTs methylate histone lysines

Biological Process

histone H3-K4 methylation

Molecular Function

RNA binding
protein binding
histone-lysine N-methyltransferase activity
histone methyltransferase activity (H3-K4 specific)

Cellular Component

nucleoplasm
chromosome
cytosol
nuclear speck
histone methyltransferase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000267197
Coding exons: 17
Length: 28477
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	4.67	706	1.15e+3	0.613	0.0000769	12303
Missense (PolyPhen)		91	187.96	0.48414		1927
Synonymous	-1.06	551	520	1.06	0.0000389	4098
Loss of Function	6.74	4	60.6	0.0660	0.00000343	714

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: Histone methyltransferase that specifically methylates 'Lys-4' of histone H3, when part of the SET1 histone methyltransferase (HMT) complex, but not if the neighboring 'Lys- 9' residue is already methylated. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. The non-overlapping localization with SETD1A suggests that SETD1A and SETD1B make non-redundant contributions to the epigenetic control of chromatin structure and gene expression. Specifically tri-methylates 'Lys-4' of histone H3 in vitro.;

Recessive Scores

pRec: 0.106

Intolerance Scores

RVIS EVS: 0.2
RVIS percentile EVS: 67.43

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.975

Gene Damage Prediction

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