KANSL1

protein-coding

KAT8 regulatory NSL complex subunit 1, the group of NSL histone acetyltransferase complex

Gene summary

This gene encodes a nuclear protein that is a subunit of two protein complexes involved with histone acetylation, the MLL1 complex and the NSL1 complex. The encoded protein has been implicated in a variety of cellular processes including enhancer regulation, cell proliferation, and mitosis. Mutations in this gene are associated with Koolen-de Vries Syndrome. [provided by RefSeq, May 2022]

Previous symbols:

KIAA1267

MANE transcript

NM_015443.4

Inheritance

ClinVar variants

P:139U:529B:560

Top phenotype

Koolen-de Vries syndrome

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr17:46,029,916-46,225,389

External References & Databases

Ensembl (ENSG00000120071)

Transcript & Mutation Effects

hg38 • Region Span ~195.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Koolen-de Vries syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012496

Submitter: G2P

Koolen-de Vries syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012496

Submitter: Ambry Genetics

Koolen-de Vries syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012496

Submitter: ClinGen

*KANSL1* was first reported in relation to autosomal dominant Koolen-de Vries syndrome (KdVS) in 2012 (Kooken et al. and Zollino et al., PMIDs: 22544363, 22544367). Prior to its association with KdVS, *KANSL1* was known to be one of the protein-coding genes deleted in patients with 17q21.31 deletion syndrome (PMIDs: 16906163, 16906164). KdVS is caused by pathogenic sequence variants in *KANSL1* or by 17q21.31 microdeletions encompassing *KANSL1* (PMIDs: 22544363, 22544367). KdVS is characterized by intellectual disability and/or developmental delay, hypotonia, speech and language delay, dysmorphic features, and behavioral disorders including autism and attention deficit hyperactivity disorder (PMIDs: 22544363, 22544367, 26306646). Truncating variants, including nonsense, frameshift, and splice site variants, have been identified in over 20 individuals with KdVS reported in 6 publications (PMIDs: 22544363, 22544367, 26306646, 30293248, 33361104, 33393407). The disease mechanism is haploinsufficiency. This gene-disease relationship is also supported by experimental evidence, including non-human model organisms, and functional in vitro studies (PMID: 28704368). In summary, *KANSL1* is definitively associated with Koolen-de Vries syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 18, 2022 (SOP Version 8).

Koolen-de Vries syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012496

Submitter: PanelApp Australia

Koolen-de Vries syndrome due to a point mutationSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018217

Submitter: Orphanet

Koolen-de Vries syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012496

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Koolen-de Vries syndromeAD

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Genitourinary; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 22482802; 22544363; 26306646; 28440867

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KANSL1 variants in ClinVar

16 Conditions Cataloged

Koolen-de Vries syndromeTotal: 1106

not providedTotal: 295

not specifiedTotal: 221

Inborn genetic diseasesTotal: 181

KANSL1-related disorderTotal: 29

Intellectual disabilityTotal: 7

See casesTotal: 3

Dystonia, early-onset, and/or spastic paraplegiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015443.4. 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			7 clinvar	280 clinvar	3 clinvar	290
missense	2 clinvar	8 clinvar	486 clinvar	248 clinvar	27 clinvar	771
nonsense	16 clinvar	13 clinvar	10 clinvar	1 clinvar		40
start loss			1 clinvar			1
frameshift	51 clinvar	29 clinvar	18 clinvar			98
splice donor/acceptor (+/-2bp)	10 clinvar	10 clinvar	7 clinvar	1 clinvar		28
Total	79	60	529	530	30	1228

Highest pathogenic variant AF is 0.00002912045

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 65 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015443.4	RefSeq	NP_056258.1	14	MANE Select
ENST00000432791.7	Ensembl	ENSP00000387393.3	14	MANE Select
NM_001193465.2	RefSeq	NP_001180394.1	14	Standard
NM_001193466.2	RefSeq	NP_001180395.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pathways Affected in Adenoid Cystic Carcinoma
Chromatin modifying enzymes
HATs acetylate histones
Chromatin organization

Biological Process

histone H4-K5 acetylation
histone H4-K8 acetylation
histone H4-K16 acetylation

Molecular Function

protein binding
histone acetyltransferase binding
histone acetyltransferase activity (H4-K5 specific)
histone acetyltransferase activity (H4-K8 specific)
histone acetyltransferase activity (H4-K16 specific)

Cellular Component

histone acetyltransferase complex
condensed chromosome kinetochore
nucleus
nucleoplasm
NSL complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262419
Coding exons: 14
Length: 195452
Individuals with no LoFs: 125711
Homozygous LoFs: 0
Heterozygous LoFs: 37
Defined: 125748
p: 0.000147

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.23	551	638	0.863	0.0000372	7091
Missense (PolyPhen)		144	227.12	0.63403		2429
Synonymous	-0.806	258	242	1.07	0.0000134	2286
Loss of Function	5.75	6	49.8	0.120	0.00000327	531

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00050	0.00050	rare
East Asian	0	0.0	absent
Finnish	0.00060	0.00060	rare
European (Non-Finnish)	0.00012	0.00011	rare
South Asian	0.00016	0.00016	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: As part of the NSL complex it is involved in acetylation of nucleosomal histone H4 on several lysine residues and therefore may be involved in the regulation of transcription. {ECO:0000269|PubMed:20018852, ECO:0000269|PubMed:22547026}.;

Recessive Scores

pRec: 0.137

Intolerance Scores

RVIS EVS: -0.32
RVIS percentile EVS: 30.95

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High