SETD1A

protein-coding

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

Gene summary

The protein encoded by this gene is a component of a histone methyltransferase (HMT) complex that produces mono-, di-, and trimethylated histone H3 at Lys4. Trimethylation of histone H3 at lysine 4 (H3K4me3) is a chromatin modification known to generally mark the transcription start sites of active genes. The protein contains SET domains, a RNA recognition motif domain and is a member of the class V-like SAM-binding methyltransferase superfamily. [provided by RefSeq, Dec 2016]

MANE transcript

NM_014712.3

Inheritance

ClinVar variants

P:92U:544B:255

Top phenotype

Epilepsy, early-onset 2, with or without developmental delay; Neurodevelopmental disorder with speech impairment and dysmorphic facies

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr16:30,957,294-30,984,664

External References & Databases

Ensembl (ENSG00000099381)

Transcript & Mutation Effects

hg38 • Region Span ~27.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

epilepsy, early-onset, with or without developmental delayLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0030005

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with speech impairment and dysmorphic faciesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033630

Submitter: Labcorp Genetics (formerly Invitae)

epilepsy, early-onset, with or without developmental delayLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0030005

Submitter: Ambry Genetics

neurodevelopmental disorder with speech impairment and dysmorphic faciesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033630

Submitter: G2P

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Epilepsy, early-onset 2, with or without developmental delay; Neurodevelopmental disorder with speech impairment and dysmorphic faciesAD

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: 29463886; 26974950; 31197650; 32346159

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SETD1A variants in ClinVar

14 Conditions Cataloged

not providedTotal: 397

Inborn genetic diseasesTotal: 346

not specifiedTotal: 114

Neurodevelopmental disorder with speech impairment and dysmorphic faciesTotal: 98

SETD1A-related disorderTotal: 79

Epilepsy, early-onset, with or without developmental delayTotal: 63

SchizophreniaTotal: 6

See casesTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014712.3. 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		1 clinvar	5 clinvar	139 clinvar	4 clinvar	149
missense	3 clinvar	15 clinvar	523 clinvar	110 clinvar	1 clinvar	652
nonsense	9 clinvar	16 clinvar	3 clinvar			28
start loss						0
frameshift	25 clinvar	18 clinvar	7 clinvar			50
splice donor/acceptor (+/-2bp)	2 clinvar	3 clinvar	6 clinvar	1 clinvar		12
Total	39	53	544	250	5	891

Highest pathogenic variant AF is 0.00006915832

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014712.3	RefSeq	NP_055527.1	18	MANE Select
ENST00000262519.14	Ensembl	ENSP00000262519.8	18	MANE Select
ENST00000452917.3	Ensembl	ENSP00000391408.3	2	Standard
ENST00000682768.1	Ensembl	ENSP00000508271.1	5	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

regulation of megakaryocyte differentiation
histone H3-K4 methylation
regulation of hematopoietic stem cell differentiation
regulation of chromatin organization

Molecular Function

RNA binding
protein binding
beta-catenin binding
transcription factor binding
histone-lysine N-methyltransferase activity

Cellular Component

nuclear chromatin
nucleus
nucleoplasm
nuclear speck
histone methyltransferase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262519
Coding exons: 18
Length: 27823
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125748
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.83	922	1.09e+3	0.844	0.0000756	10843
Missense (PolyPhen)		93	139.34	0.66744		1308
Synonymous	-4.19	579	464	1.25	0.0000328	3652
Loss of Function	7.15	4	67.2	0.0595	0.00000372	747

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000066	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.000046	0.000044	rare
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 SETD1B suggests that SETD1A and SETD1B make non-redundant contributions to the epigenetic control of chromatin structure and gene expression. {ECO:0000269|PubMed:12670868}.;

Intolerance Scores

LoFtool: 0.00654
RVIS EVS: -2.93
RVIS percentile EVS: 0.56

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.988

Gene Damage Prediction

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