SETD1A

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

Basic information

Region (hg38): 16:30957294-30984664

Links

ENSG00000099381 ∙ NCBI:9739 ∙ OMIM:611052 ∙ HGNC:29010 ∙ Uniprot:O15047 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• intellectual disability, autosomal dominant 40 (Strong), mode of inheritance: AD
• epilepsy, early-onset, with or without developmental delay (Limited), mode of inheritance: AD
• neurodevelopmental disorder with speech impairment and dysmorphic facies (Strong), mode of inheritance: AD
• epilepsy, early-onset, with or without developmental delay (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Epilepsy, early-onset 2, with or without developmental delay; Neurodevelopmental disorder with speech impairment and dysmorphic facies	AD	General	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	Craniofacial; Musculoskeletal; Neurologic	29463886; 26974950; 31197650; 32346159

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SETD1A gene.

• not provided (5 variants)
• Schizophrenia (5 variants)
• Neurodevelopmental disorder with speech impairment and dysmorphic facies (3 variants)
• Inborn genetic diseases (3 variants)
• Neurodevelopmental disorder (1 variants)
• Epilepsy, early-onset, with or without developmental delay (1 variants)
• Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SETD1A gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	64	4	69
missense		4	189	46	3	242
nonsense	6	6	2			14
start loss						0
frameshift	11	9	5			25
inframe indel			7	4	1	12
splice donor/acceptor (+/-2bp)	1	3	1			5
splice region		1	5	3		9
non coding				1	2	3
Total	18	22	205	115	10

Highest pathogenic variant AF is 0.00000660

Variants in SETD1A

This is a list of pathogenic ClinVar variants found in the SETD1A region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
16-30958738-C-T		Neurodevelopmental disorder with speech impairment and dysmorphic facies	Likely pathogenic (Oct 04, 2022)
16-30958765-G-A		Inborn genetic diseases	Uncertain significance (Jan 08, 2024)
16-30958769-C-T			Uncertain significance (Jan 25, 2024)
16-30958773-C-G		Inborn genetic diseases	Uncertain significance (Jun 29, 2021)
16-30958777-C-T		Epilepsy, early-onset, with or without developmental delay	Likely pathogenic (Feb 18, 2020)
16-30958833-G-A			Likely benign (Nov 28, 2018)
16-30958834-C-T			Likely benign (Jan 01, 2024)
16-30958835-C-T		Inborn genetic diseases	Uncertain significance (Oct 26, 2022)
16-30958869-C-T		SETD1A-related disorder	Likely benign (Jun 07, 2019)
16-30959089-A-G		Neurodevelopmental disorder with speech impairment and dysmorphic facies	Likely pathogenic (Feb 01, 2023)
16-30959092-ACT-A		Inborn genetic diseases	Pathogenic (Dec 04, 2023)
16-30959103-A-G		Inborn genetic diseases	Uncertain significance (Oct 22, 2021)
16-30959107-C-T			Uncertain significance (Feb 27, 2024)
16-30959118-C-A		Inborn genetic diseases	Uncertain significance (Apr 10, 2023)
16-30959129-C-T			Likely benign (Apr 09, 2018)
16-30959130-C-T		Inborn genetic diseases	Conflicting classifications of pathogenicity (Sep 06, 2023)
16-30959134-G-A			Uncertain significance (Mar 02, 2023)
16-30959145-T-A			Uncertain significance (Jul 07, 2020)
16-30959145-T-C		Inborn genetic diseases	Uncertain significance (Aug 10, 2021)
16-30959153-CA-C		Inborn genetic diseases	Pathogenic (Jun 06, 2017)
16-30959155-G-T			Uncertain significance (Jul 26, 2021)
16-30959160-T-G		Inborn genetic diseases	Uncertain significance (Feb 06, 2023)
16-30959164-C-T		Inborn genetic diseases	Uncertain significance (Nov 19, 2021)
16-30959190-A-G		Inborn genetic diseases	Uncertain significance (Sep 21, 2021)
16-30961265-A-C		SETD1A-related disorder	Uncertain significance (Jan 21, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SETD1A	protein_coding	protein_coding	ENST00000262519	18	27823

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	1.57e-8	125738	0	10	125748	0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.83	922	1.09e+3	0.844	0.0000756	10843
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000948	0.0000904
Ashkenazi Jewish	0.000101	0.0000992
East Asian	0.00	0.00
Finnish	0.0000926	0.0000924
European (Non-Finnish)	0.0000464	0.0000439
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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}.
• Pathway: Lysine degradation - Homo sapiens (human);Histone Modifications;Gene expression (Transcription);Generic Transcription Pathway;PKMTs methylate histone lysines;RNA Polymerase II Transcription;RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function;Chromatin modifying enzymes;Lysine metabolism;Chromatin organization;Transcriptional regulation by RUNX1 (Consensus)

Intolerance Scores

• loftool: 0.00654
• rvis_EVS: -2.93
• rvis_percentile_EVS: 0.56

Haploinsufficiency Scores

• pHI: 0.319
• hipred: Y
• hipred_score: 0.743
• ghis: 0.641

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.988

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Setd1a
• Phenotype: immune system phenotype; skeleton phenotype; embryo phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); cellular phenotype; homeostasis/metabolism phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: regulation of megakaryocyte differentiation;histone H3-K4 methylation;regulation of hematopoietic stem cell differentiation;regulation of chromatin organization
• Cellular component: nuclear chromatin;nucleus;nucleoplasm;nuclear speck;histone methyltransferase complex;Set1C/COMPASS complex
• Molecular function: RNA binding;protein binding;beta-catenin binding;transcription factor binding;histone-lysine N-methyltransferase activity;histone methyltransferase activity (H3-K4 specific)