WDR4

protein-coding

WD repeat domain 4, the group of WD repeat domain containing

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 gene is excluded as a candidate for a form of nonsyndromic deafness (DFNB10), but is still a candidate for other disorders mapped to 21q22.3 as well as for the development of Down syndrome phenotypes. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, May 2012]

MANE transcript

NM_018669.6

Inheritance

ClinVar variants

P:18U:141B:99

Top phenotype

Galloway-Mowat syndrome 6

gnomAD constraint

pLI —, LoF o/e 0.73

Max pathogenic AF

—

Genomic locus

chr21:42,843,094-42,879,568

External References & Databases

Ensembl (ENSG00000160193)

Transcript & Mutation Effects

hg38 • Region Span ~36.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Galloway-Mowat syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009627

Submitter: Orphanet

microcephaly, growth deficiency, seizures, and brain malformationsMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032690

Submitter: Ambry Genetics

Galloway-Mowat syndrome 6LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032691

Submitter: G2P

microcephaly, growth deficiency, seizures, and brain malformationsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032690

Submitter: PanelApp Australia

microcephaly, growth deficiency, seizures, and brain malformationsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032690

Submitter: Labcorp Genetics (formerly Invitae)

Galloway-Mowat syndrome 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032691

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Galloway-Mowat syndrome 6AR

Manifestation: Craniofacial; Endocrine; Neurologic; Renal

Intervention: Endocrine; Renal

Rationale: Endocrine manifestations such as growth hormone deficiency have been observed, and awareness may allow prompt recognition and treatment; Among other features, the condition may include renal disease, and use of immunosuppressive treatments has been described as necessary in at least one patient

Refs: 26416026; 28617965; 29597095; 30079490

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WDR4 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 223

Inborn genetic diseasesTotal: 118

WDR4-related disorderTotal: 33

not specifiedTotal: 16

Galloway-Mowat syndrome 6Total: 14

Microcephaly, growth deficiency, seizures, and brain malformationsTotal: 11

Galloway-Mowat syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018669.6. 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				76 clinvar	4 clinvar	80
missense	1 clinvar	4 clinvar	132 clinvar	19 clinvar		156
nonsense	2 clinvar	1 clinvar				3
start loss		1 clinvar	1 clinvar			2
frameshift	4 clinvar	1 clinvar	1 clinvar			6
splice donor/acceptor (+/-2bp)		4 clinvar	7 clinvar			11
Total	7	11	141	95	4	258

Highest pathogenic variant AF is 0.000013639469

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 51 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018669.6	RefSeq	NP_061139.2	11	MANE Select
ENST00000398208.3	Ensembl	ENSP00000381266.2	11	MANE Select
NM_001260474.2	RefSeq	NP_001247403.1	11	Standard
NM_001260475.2	RefSeq	NP_001247404.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

tRNA modification in the nucleus and cytosol
tRNA processing
Metabolism of RNA

Biological Process

tRNA modification
tRNA (guanine-N7)-methylation

Molecular Function

protein binding
tRNA (guanine-N7-)-methyltransferase activity

Cellular Component

nucleus
nucleoplasm
cytosol
tRNA methyltransferase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000398208
Coding exons: 11
Length: 36475
Individuals with no LoFs: 125719
Homozygous LoFs: 0
Heterozygous LoFs: 29
Defined: 125748
p: 0.000115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.02	304	258	1.18	0.0000165	2636
Missense (PolyPhen)		64	60.167	1.0637		695
Synonymous	-1.47	134	114	1.18	0.00000807	808
Loss of Function	1.16	15	20.7	0.725	9.73e-7	219

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00021	0.00018	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00011	0.000097	rare
South Asian	0.00017	0.00016	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for the formation of N(7)-methylguanine at position 46 (m7G46) in tRNA. In the complex, it is required to stabilize and induce conformational changes of the catalytic subunit. {ECO:0000255|HAMAP-Rule:MF_03056, ECO:0000269|PubMed:12403464}.;

Recessive Scores

pRec: 0.103

Intolerance Scores

LoFtool: 0.820
RVIS EVS: -0.93
RVIS percentile EVS: 9.72

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.939

Gene Damage Prediction

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