WDR5

protein-coding

WD repeat domain 5, the group of WD repeat domain containing|WRAD complex|ATAC complex|NSL histone acetyltransferase complex|Cilia and flagella associated

Gene summary

This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This protein contains 7 WD repeats. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

MANE transcript

NM_017588.3

Inheritance

ClinVar variants

P:4U:40B:5

Top phenotype

neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr9:134,135,365-134,159,968

External References & Databases

Ensembl (ENSG00000196363)

Transcript & Mutation Effects

hg38 • Region Span ~24.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

congenital heart diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

WDR5 was first reported in relation to autosomal dominant congenital heart disease in 2020 (Liu et al., PMID: 33131162). 2 variants (missense) that have been reported in 2 probands in 2 publications (PMIDs: 33131162, 33442022) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (expression data; PMID: 30377171, NCBI fetal expression). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 7/8/2024 (SOP Version 10).

neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WDR5 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 26

not specifiedTotal: 15

Neurodevelopmental disorderTotal: 1

WDR5-related neurodevelopmental delayTotal: 1

WDR5-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017588.3. 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	4 clinvar		5
missense	2 clinvar	2 clinvar	32 clinvar	1 clinvar		37
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			7 clinvar			7
Total	2	2	40	5	0	49

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 45 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017588.3	RefSeq	NP_060058.1	13	MANE Select
ENST00000358625.4	Ensembl	ENSP00000351446.3	13	MANE Select
NM_001384409.1	RefSeq	NP_001371338.1	13	Standard
NM_001384410.1	RefSeq	NP_001371339.1	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cushing,s syndrome - Homo sapiens (human)
Gene expression (Transcription)
Generic Transcription Pathway
Post-translational protein modification
Metabolism of proteins

Biological Process

skeletal system development
neuron projection development
positive regulation of gluconeogenesis by positive regulation of transcription from RNA polymerase II promoter
post-translational protein modification
histone H3 acetylation

Molecular Function

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

Cellular Component

histone acetyltransferase complex
nucleus
nucleoplasm
Ada2/Gcn5/Ada3 transcription activator complex
histone methyltransferase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000358625
Coding exons: 13
Length: 24607
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	3.39	63	197	0.320	0.0000115	2180
Missense (PolyPhen)		7	69.676	0.10047		796
Synonymous	0.257	82	85.0	0.965	0.00000615	624
Loss of Function	4.54	0	24.0	0.00	0.00000122	269

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: Contributes to histone modification. May position the N- terminus of histone H3 for efficient trimethylation at 'Lys-4'. As part of the MLL1/MLL complex it is involved in methylation and dimethylation at 'Lys-4' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. May regulate osteoblasts differentiation. {ECO:0000269|PubMed:16600877, ECO:0000269|PubMed:16829960, ECO:0000269|PubMed:19103755, ECO:0000269|PubMed:19556245, ECO:0000269|PubMed:20018852}.;

Recessive Scores

pRec: 0.178

Intolerance Scores

RVIS EVS: -0.25
RVIS percentile EVS: 35.42

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.553

Gene Damage Prediction

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