WDR4

Summary

WDR4 (WDR4 tRNA N7-guanosine methyltransferase non-catalytic subunit, HGNC:12756) is a protein-coding gene on chromosome 21q22.3, encoding tRNA (guanine-N(7)-)-methyltransferase non-catalytic subunit WDR4 (P57081). Non-catalytic component of the METTL1-WDR4 methyltransferase complex required for the formation of N(7)-methylguanine in a subset of RNA species, such as tRNAs, mRNAs and microRNAs (miRNAs). It is a selective cancer dependency (DepMap: 32.5% of cell lines).

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.

Source: NCBI Gene 10785 — RefSeq curated summary.

At a glance

• Gene–disease (curated): microcephaly, growth deficiency, seizures, and brain malformations (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 357 total — 10 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 73
• Cancer dependency (DepMap): dependent in 32.5% of screened cell lines
• MANE Select transcript: NM_018669

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12756
Approved symbol	WDR4
Name	WDR4 tRNA N7-guanosine methyltransferase non-catalytic subunit
Location	21q22.3
Locus type	gene with protein product
Status	Approved
Aliases	TRM82, TRMT82, Wuho
Ensembl gene	ENSG00000160193
Ensembl biotype	protein_coding
OMIM	605924
Entrez	10785

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 15 protein_coding, 5 protein_coding_CDS_not_defined

ENST00000330317, ENST00000398208, ENST00000463902, ENST00000470658, ENST00000476326, ENST00000479429, ENST00000492742, ENST00000899716, ENST00000899717, ENST00000899718, ENST00000899719, ENST00000931734, ENST00000931735, ENST00000931736, ENST00000931737, ENST00000931738, ENST00000931739, ENST00000931740, ENST00000949296, ENST00000949297

RefSeq mRNA: 6 — MANE Select: NM_018669 NM_001260474, NM_001260475, NM_001260476, NM_001260477, NM_018669, NM_033661

CCDS: CCDS13691

Canonical transcript exons

ENST00000398208 — 11 exons

Exon	Start	End
ENSE00001138597	42879407	42879539
ENSE00003486103	42873551	42873691
ENSE00003511519	42855682	42855780
ENSE00003540633	42852255	42852324
ENSE00003552431	42849226	42850242
ENSE00003570160	42853569	42853752
ENSE00003599130	42862282	42862394
ENSE00003606199	42854562	42854626
ENSE00003641564	42863440	42863596
ENSE00003690805	42876702	42876767
ENSE00003694162	42859662	42859722

Expression profiles

Bgee: expression breadth ubiquitous, 214 present calls, max score 87.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.0031 / max 185.2240, expressed in 1790 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190660	20.4579	1789
190661	0.5453	321

Top tissues by expression

279 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gingival epithelium	UBERON:0001949	87.60	gold quality
mucosa of transverse colon	UBERON:0004991	83.88	gold quality
gingiva	UBERON:0001828	83.87	gold quality
esophagus squamous epithelium	UBERON:0006920	83.01	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.87	gold quality
lower esophagus mucosa	UBERON:0035834	81.01	gold quality
esophagus mucosa	UBERON:0002469	80.74	gold quality
gastrocnemius	UBERON:0001388	78.77	gold quality
pancreatic ductal cell	CL:0002079	78.52	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.51	gold quality
stromal cell of endometrium	CL:0002255	78.30	gold quality
esophagus	UBERON:0001043	78.03	gold quality
body of pancreas	UBERON:0001150	78.02	gold quality
vagina	UBERON:0000996	77.75	gold quality
epithelium of esophagus	UBERON:0001976	77.72	gold quality
muscle of leg	UBERON:0001383	77.67	gold quality
squamous epithelium	UBERON:0006914	77.65	gold quality
ganglionic eminence	UBERON:0004023	77.53	gold quality
ectocervix	UBERON:0012249	77.29	gold quality
lymph node	UBERON:0000029	77.24	gold quality
monocyte	CL:0000576	77.11	gold quality
right lobe of liver	UBERON:0001114	76.92	gold quality
right ovary	UBERON:0002118	76.88	gold quality
cortical plate	UBERON:0005343	76.87	gold quality
body of uterus	UBERON:0009853	76.78	gold quality
mononuclear cell	CL:0000842	76.74	gold quality
pancreas	UBERON:0001264	76.72	gold quality
skin of leg	UBERON:0001511	76.70	gold quality
leukocyte	CL:0000738	76.66	gold quality
tonsil	UBERON:0002372	76.64	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.01
E-MTAB-7249	no	28.61

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

23 targeting WDR4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-6859-5P	98.99	68.07	2049
HSA-MIR-6770-5P	98.97	66.76	1853
HSA-MIR-6889-3P	98.84	67.35	1198
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-5006-5P	98.79	66.92	1246
HSA-MIR-4635	98.74	67.63	1339
HSA-MIR-384	98.71	67.34	1229
HSA-MIR-6529-3P	98.68	66.76	1020
HSA-MIR-6868-3P	98.63	69.64	2259
HSA-MIR-1248	98.47	67.54	1314
HSA-MIR-138-5P	98.43	70.49	1292
HSA-MIR-6864-5P	98.38	66.59	1079
HSA-MIR-6509-3P	98.32	67.33	1343
HSA-MIR-6765-3P	97.83	64.59	1165
HSA-MIR-5571-3P	97.80	66.07	640
HSA-MIR-6131	97.22	66.72	960
HSA-MIR-1306-5P	97.11	64.04	755
HSA-MIR-6772-3P	97.04	65.89	784
HSA-MIR-598-5P	92.45	70.36	75

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 32.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 17)

• Combined autozygome/exome analysis revealed a novel missense mutation in WDR4 as the likely causal variant of Primordial dwarfism (PMID:26416026)
• regulates FEN1’s potential DNA cleavage threat near the site of replication (PMID:26751069)
• We report here 2 sisters harboring compound heterozygous variants of WDR4. Their phenotype differs from that of the first 2 described patients: they both have a severe microcephaly but only one of the 2 sisters had a head circumference at birth below -2 SD, their intellectual deficiency is less severe, and they have a growth hormone deficiency and a partial hypogonadotropic hypogonadotropism (PMID:28617965)
• WDR4 is an oncoprotein that negatively regulates PML via ubiquitination to promote lung cancer progression by fostering an immunosuppressive and prometastatic tumor microenvironment (PMID:28691927)
• WDR4 is an additional example of a gene that encodes a tRNA modifying enzyme and gives rise to Galloway-Mowat syndrome, if mutated (PMID:30079490)
• Aberrant expression of WDR4 affects the clinical significance of cancer immunity in pan-cancer. (PMID:34282052)
• N(7)-Methylguanosine tRNA modification enhances oncogenic mRNA translation and promotes intrahepatic cholangiocarcinoma progression. (PMID:34352206)
• METTL1/WDR4-mediated m(7)G tRNA modifications and m(7)G codon usage promote mRNA translation and lung cancer progression. (PMID:34371184)
• Structures and mechanisms of tRNA methylation by METTL1-WDR4. (PMID:36599982)
• Structural basis of regulated m[7]G tRNA modification by METTL1-WDR4. (PMID:36599985)
• Wdr4 promotes cerebellar development and locomotion through Arhgap17-mediated Rac1 activation. (PMID:36681682)
• Association of RNA m[7]G Modification Gene Polymorphisms with Pediatric Glioma Risk. (PMID:36733406)
• METTL1/WDR4-mediated tRNA m[7]G modification and mRNA translation control promote oncogenesis and doxorubicin resistance. (PMID:37185458)
• WDR4/TRIM28 is a novel molecular target linked to lenvatinib resistance that helps retain the stem characteristics in hepatocellular carcinomas. (PMID:37279851)
• PTPN23 ubiquitination by WDR4 suppresses EGFR and c-MET degradation to define a lung cancer therapeutic target. (PMID:37821451)
• WDR4 promotes HCC pathogenesis through N[7]-methylguanosine by regulating and interacting with METTL1. (PMID:38493882)
• Cilia defects upon loss of WDR4 are linked to proteasomal hyperactivity and ubiquitin shortage. (PMID:39251572)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	wdr4	ENSDARG00000090581
mus_musculus	Wdr4	ENSMUSG00000024037
rattus_norvegicus	Wdr4	ENSRNOG00000001181
drosophila_melanogaster	wuho	FBGN0029857
caenorhabditis_elegans		WBGENE00022420

Protein

Protein identifiers

tRNA (guanine-N(7)-)-methyltransferase non-catalytic subunit WDR4 — P57081 (reviewed: P57081)

Alternative names: Protein Wuho homolog, WD repeat-containing protein 4

All UniProt accessions (1): P57081

UniProt curated annotations — full annotation on UniProt →

Function. Non-catalytic component of the METTL1-WDR4 methyltransferase complex required for the formation of N(7)-methylguanine in a subset of RNA species, such as tRNAs, mRNAs and microRNAs (miRNAs). In the METTL1-WDR4 methyltransferase complex, WDR4 acts as a scaffold for tRNA-binding. Required for the formation of N(7)-methylguanine at position 46 (m7G46) in a large subset of tRNAs that contain the 5’-RAGGU-3’ motif within the variable loop. M7G46 interacts with C13-G22 in the D-loop to stabilize tRNA tertiary structure and protect tRNAs from decay. Also required for the formation of N(7)-methylguanine at internal sites in a subset of mRNAs. Also required for methylation of a specific subset of miRNAs, such as let-7. Independently of METTL1, also plays a role in genome stability: localizes at the DNA replication site and regulates endonucleolytic activities of FEN1.

Subunit / interactions. Non-catalytic component of the METTL1-WDR4 complex, composed of METTL1 and WDR4. Interacts with FEN1; the interaction is direct.

Subcellular location. Nucleus. Chromosome.

Disease relevance. Galloway-Mowat syndrome 6 (GAMOS6) [MIM:618347] A form of Galloway-Mowat syndrome, a severe renal-neurological disease characterized by early-onset nephrotic syndrome associated with microcephaly, central nervous system abnormalities, developmental delays, and a propensity for seizures. Brain anomalies include gyration defects ranging from lissencephaly to pachygyria and polymicrogyria, and cerebellar hypoplasia. Most patients show facial dysmorphism characterized by a small, narrow forehead, large/floppy ears, deep-set eyes, hypertelorism and micrognathia. Additional variable features are visual impairment and arachnodactyly. Most patients die in early childhood. GAMOS6 is an autosomal recessive form with onset in infancy or early childhood. Affected individuals manifest microcephaly, global developmental delay, variable degrees of intellectual disability, and growth deficiency. Renal impairment may be age-dependent or may not be present. The disease is caused by variants affecting the gene represented in this entry. Microcephaly, growth deficiency, seizures, and brain malformations (MIGSB) [MIM:618346] An autosomal recessive disorder characterized by intrauterine growth retardation, postnatal growth deficiency, microcephaly, facial dysmorphism, early-onset seizures, brain malformations such as partial agenesis of the corpus callosum and simplified gyration, and poor or absent psychomotor development. The disease is caused by variants affecting the gene represented in this entry.

Induction. Amplified and overexpressed in a number of cancers (at protein level).

Pathway. tRNA modification; N(7)-methylguanine-tRNA biosynthesis.

Miscellaneous. In the context of cancer, overexpression of the METTL1-WDR4 methyltransferase complex promotes cancer progression by driving oncogenic transformation. The METTL1-WDR4 methyltransferase complex drives oncogenesis by mediating the formation of N(7)-methylguanine at position 46 (m7G46) in some tRNAs, in particular Arg-TCT-4-1 (TRR-TCT4-1), leading to increased translation of mRNAs, including cell cycle regulators that are enriched in the corresponding AGA codon.

Similarity. Belongs to the WD repeat TRM82 family.

Isoforms (3)

UniProt ID	Names	Canonical?
P57081-1	1	yes
P57081-2	2
P57081-3	3

RefSeq proteins (6): NP_001247403, NP_001247404, NP_001247405, NP_001247406, NP_061139, NP_387510 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR028884	Trm82	Family
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily

Pfam: PF00400

UniProt features (81 total): strand 30, mutagenesis site 12, sequence variant 7, repeat 7, helix 7, turn 6, sequence conflict 4, modified residue 3, splice variant 2, initiator methionine 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
8H0N	X-RAY DIFFRACTION	1.8
8D58	X-RAY DIFFRACTION	2.47
7U20	X-RAY DIFFRACTION	3.1
8CTH	ELECTRON MICROSCOPY	3.3
8EG0	ELECTRON MICROSCOPY	3.53
8CTI	ELECTRON MICROSCOPY	3.6
8D9K	ELECTRON MICROSCOPY	3.72
8D9L	ELECTRON MICROSCOPY	4.04

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P57081-F1	87.15	0.71

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 2, 391, 411

Mutagenesis-validated functional residues (12):

Position	Phenotype
83	slightly reduced formation of n(7)-methylguanine in trnas.
103–104	abolished formation of n(7)-methylguanine in trnas.
103	does not affect formation of n(7)-methylguanine in trnas.
104	does not affect formation of n(7)-methylguanine in trnas.
122	does not affect formation of n(7)-methylguanine in trnas.
147	reduced formation of n(7)-methylguanine in trnas.
165	abolished formation of n(7)-methylguanine in trnas.
166	abolished formation of n(7)-methylguanine in trnas.
167	abolished formation of n(7)-methylguanine in trnas.
170	reduced formation of n(7)-methylguanine in trnas.
365	reduced formation of n(7)-methylguanine in trnas.
371	slightly reduced formation of n(7)-methylguanine in trnas.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6782315	tRNA modification in the nucleus and cytosol

MSigDB gene sets: 282 (showing top): RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_TRNA_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_RNA_METHYLATION, WEI_MYCN_TARGETS_WITH_E_BOX, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_RNA_MODIFICATION, GOBP_TRNA_METHYLATION, GOBP_DNA_DAMAGE_RESPONSE, DODD_NASOPHARYNGEAL_CARCINOMA_UP, FISCHER_DREAM_TARGETS, BASAKI_YBX1_TARGETS_UP, chr21q22

GO Biological Process (6): tRNA modification (GO:0006400), DNA damage response (GO:0006974), tRNA (guanine-N7)-methylation (GO:0106004), tRNA processing (GO:0008033), RNA (guanine-N7)-methylation (GO:0036265), tRNA stabilization (GO:0036416)

GO Molecular Function (3): enzyme activator activity (GO:0008047), protein binding (GO:0005515), tRNA methyltransferase activator activity (GO:0141106)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), cytosol (GO:0005829), tRNA methyltransferase complex (GO:0043527), tRNA (m7G46) methyltransferase complex (GO:0106143)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
tRNA processing	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
tRNA processing	1
RNA modification	1
cellular response to stress	1
tRNA methylation	1
RNA (guanine-N7)-methylation	1
RNA processing	1
tRNA metabolic process	1
RNA methylation	1
regulation of tRNA stability	1
RNA stabilization	1
negative regulation of tRNA catabolic process	1
catalytic activity	1
enzyme regulator activity	1
molecular function activator activity	1
binding	1
enzyme activator activity	1
methyltransferase activity	1
methyltransferase regulator activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular membraneless organelle	1
cytoplasm	1
methyltransferase complex	1
tRNA methyltransferase complex	1

Protein interactions and networks

STRING

1894 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WDR4	METTL1	Q9UBP6	998
WDR4	FTSJ1	Q9UET6	744
WDR4	TRMT61A	Q96FX7	744
WDR4	TRMT10A	Q8TBZ6	742
WDR4	ADAT3	Q96EY9	734
WDR4	TRMT6	Q9UJA5	718
WDR4	BUD23	O43709	718
WDR4	NSUN2	Q08J23	717
WDR4	TRMT112	Q9UI30	710
WDR4	NDUFV3	P56181	702
WDR4	PKNOX1	P55347	674
WDR4	PUS3	Q9BZE2	666
WDR4	TRMT11	Q7Z4G4	648
WDR4	WDR73	Q6P4I2	646
WDR4	TRUB1	Q8WWH5	645

IntAct

51 interactions, top by confidence:

A	B	Type	Score
WDR4	METTL1	psi-mi:“MI:0915”(physical association)	0.910
METTL1	WDR4	psi-mi:“MI:0915”(physical association)	0.910
WDR4	FAM118A	psi-mi:“MI:0915”(physical association)	0.780
FAM118A	WDR4	psi-mi:“MI:0915”(physical association)	0.780
WDR4	RABGGTB	psi-mi:“MI:0915”(physical association)	0.720
RABGGTB	WDR4	psi-mi:“MI:0915”(physical association)	0.720
WDR4	FEN1	psi-mi:“MI:0915”(physical association)	0.660
WDR4	FEN1	psi-mi:“MI:0407”(direct interaction)	0.660
WDR4	PCNA	psi-mi:“MI:0914”(association)	0.460
TERF1	WDR4	psi-mi:“MI:0915”(physical association)	0.370
WDR4	TERF2	psi-mi:“MI:0915”(physical association)	0.370
ATXN7L1	USP27X	psi-mi:“MI:0914”(association)	0.350
METTL1	ZWINT	psi-mi:“MI:0914”(association)	0.350
WDR4	PBX2	psi-mi:“MI:0914”(association)	0.350

BioGRID (128): WDR4 (Affinity Capture-Western), METTL1 (Affinity Capture-Western), WDR4 (Two-hybrid), WDR4 (Two-hybrid), FAM118A (Two-hybrid), BIRC6 (Affinity Capture-MS), DPP8 (Affinity Capture-MS), WDR4 (Affinity Capture-MS), WDR4 (Two-hybrid), PPP2R2A (Co-fractionation), SAR1A (Co-fractionation), WDR4 (Co-fractionation), WDR4 (Co-fractionation), WDR4 (Co-fractionation), FEN1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8HX76, A0JP70, A4IG72, A7E3S5, A7Z052, D3ZW91, E9PY46, P57081, Q05B17, Q0P5H9, Q15061, Q32P44, Q3SZD4, Q3U821, Q499N3, Q4VBE8, Q5BK48, Q5F3K4, Q5RB07, Q5RBH8, Q5RD06, Q5XFW6, Q68EI0, Q6DFC6, Q6KAU8, Q6PFM9, Q6PGF3, Q6ZQL4, Q7ZVF0, Q7ZVR1, Q7ZY78, Q8BH57, Q8C5V5, Q8IWA0, Q8N0Z6, Q8NA23, Q8NAA4, Q8VC03, Q969R8, Q96KV7

Diamond homologs: A1CRF7, A4IGH4, A5E654, A6ZYC3, A7F9K1, A7TEN6, A7UVN1, B0XNT4, B3LGB9, B3MRC6, B4GXH4, B5DMC9, B5VG60, P0CS52, P0CS53, P57081, Q03774, Q0TZA1, Q1DXS8, Q2UKH7, Q4WJR4, Q5FVB6, Q6C705, Q6CQH2, Q6FVL4, Q750U8, Q7ZY78, Q9EP82, A3LPG0, A5DNM7, A7E3S5, A8XPH5, B0W8M5, B3NXQ7, B4JWS7, B4L6T9, B4MA12, B4NER4, B4PYR0, Q17CH9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

357 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	9
Uncertain significance	137
Likely benign	130
Benign	38

Top pathogenic / likely-pathogenic (19)

Variant ID	HGVS	Classification
2085363	NM_018669.6(WDR4):c.508C>T (p.Arg170Ter)	Pathogenic
2130364	NM_018669.6(WDR4):c.1159C>T (p.Gln387Ter)	Pathogenic
2297972	NM_018669.6(WDR4):c.779_786del (p.Leu260fs)	Pathogenic
2848231	NM_018669.6(WDR4):c.499G>T (p.Glu167Ter)	Pathogenic
3662701	NM_018669.6(WDR4):c.797dup (p.Val267fs)	Pathogenic
3907189	NC_000021.8:g.(44275891_44279771)_(44279833_44282391)del	Pathogenic
438741	NM_018669.6(WDR4):c.491A>C (p.Asp164Ala)	Pathogenic
438742	NM_018669.6(WDR4):c.940dup (p.Leu314fs)	Pathogenic
4762027	NM_018669.6(WDR4):c.715dup (p.Gln239fs)	Pathogenic
619602	NM_018669.6(WDR4):c.911_927dup (p.Gln310fs)	Pathogenic
2503412	NM_018669.6(WDR4):c.509_510delinsTT (p.Arg170Leu)	Likely pathogenic
2585312	NM_018669.6(WDR4):c.1A>G (p.Met1Val)	Likely pathogenic
3336333	NM_018669.6(WDR4):c.453+2_453+8delinsCAGGTGT	Likely pathogenic
3336335	NM_018669.6(WDR4):c.453+2T>C	Likely pathogenic
3337743	NM_018669.6(WDR4):c.428G>A (p.Gly143Glu)	Likely pathogenic
3377309	NM_018669.6(WDR4):c.727-331G>T	Likely pathogenic
3697312	NM_018669.6(WDR4):c.627+2T>C	Likely pathogenic
619601	NM_018669.6(WDR4):c.509G>A (p.Arg170Gln)	Likely pathogenic
619605	NM_018669.6(WDR4):c.454-2A>C	Likely pathogenic

SpliceAI

2446 predictions. Top by Δscore:

Variant	Effect	Δscore
21:42852321:CAGA:C	acceptor_gain	1.0000
21:42852325:C:CC	acceptor_gain	1.0000
21:42853563:TCTCA:T	donor_loss	1.0000
21:42853564:CTCAC:C	donor_loss	1.0000
21:42853565:TCACC:T	donor_loss	1.0000
21:42853566:CACC:C	donor_loss	1.0000
21:42853567:A:C	donor_loss	1.0000
21:42853568:C:CA	donor_loss	1.0000
21:42853612:T:TA	donor_gain	1.0000
21:42853753:C:CC	acceptor_gain	1.0000
21:42853754:T:C	acceptor_gain	1.0000
21:42853754:T:TC	acceptor_gain	1.0000
21:42853758:C:CT	acceptor_gain	1.0000
21:42853758:C:T	acceptor_gain	1.0000
21:42853760:C:CT	acceptor_gain	1.0000
21:42854624:CTT:C	acceptor_gain	1.0000
21:42862280:A:AC	donor_gain	1.0000
21:42862281:C:CC	donor_gain	1.0000
21:42862281:CT:C	donor_gain	1.0000
21:42862405:A:T	acceptor_gain	1.0000
21:42862411:C:CT	acceptor_gain	1.0000
21:42862411:C:T	acceptor_gain	1.0000
21:42862412:A:T	acceptor_gain	1.0000
21:42873601:A:AC	donor_gain	1.0000
21:42873602:C:CC	donor_gain	1.0000
21:42873602:CTGT:C	donor_gain	1.0000
21:42873690:CC:C	acceptor_gain	1.0000
21:42873691:CC:C	acceptor_gain	1.0000
21:42873691:CCT:C	acceptor_loss	1.0000
21:42873692:C:CC	acceptor_gain	1.0000

AlphaMissense

2688 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:42859719:A:C	F190L	0.998
21:42859719:A:T	F190L	0.998
21:42859721:A:G	F190L	0.998
21:42855760:C:A	W216C	0.997
21:42855760:C:G	W216C	0.997
21:42855762:A:G	W216R	0.997
21:42855762:A:T	W216R	0.997
21:42862332:G:C	S172R	0.996
21:42862332:G:T	S172R	0.996
21:42862334:T:G	S172R	0.996
21:42862342:A:G	I169T	0.996
21:42862354:C:G	R165P	0.996
21:42862351:T:A	D166V	0.995
21:42862361:C:G	A163P	0.995
21:42863516:A:T	V126D	0.995
21:42859672:G:A	S206F	0.994
21:42862299:G:C	F183L	0.994
21:42862299:G:T	F183L	0.994
21:42862301:A:G	F183L	0.994
21:42862342:A:C	I169S	0.994
21:42862360:G:T	A163D	0.994
21:42863522:C:A	G124V	0.994
21:42859713:G:C	S192R	0.993
21:42859713:G:T	S192R	0.993
21:42859715:T:G	S192R	0.993
21:42859672:G:T	S206Y	0.992
21:42855761:C:G	W216S	0.991
21:42859717:A:T	V191E	0.991
21:42862336:A:T	V171D	0.991
21:42862339:C:G	R170P	0.991

dbSNP variants (sampled 300 via entrez): RS1000060042 (21:42886495 G>A), RS1000098449 (21:42858561 G>C), RS1000102023 (21:42842962 C>G), RS1000102522 (21:42872825 T>C), RS1000106058 (21:42890406 C>A), RS1000164003 (21:42867205 A>C,G), RS1000232962 (21:42868127 C>T), RS1000325000 (21:42862900 T>C), RS1000384979 (21:42859556 A>G), RS1000444832 (21:42863096 T>C), RS1000493623 (21:42887084 C>A), RS1000516601 (21:42893039 C>G,T), RS1000536456 (21:42873029 T>C), RS1000580833 (21:42854884 G>C), RS1000710769 (21:42850777 T>C)

Disease associations

OMIM: gene MIM:605924 | disease phenotypes: MIM:618346, MIM:618347, MIM:251300

GenCC curated gene-disease

Disease	Classification	Inheritance
microcephaly, growth deficiency, seizures, and brain malformations	Strong	Autosomal recessive
Galloway-Mowat syndrome 6	Strong	Autosomal recessive
Galloway-Mowat syndrome	Supportive	Autosomal recessive

Mondo (3): microcephaly, growth deficiency, seizures, and brain malformations (MONDO:0032690), Galloway-Mowat syndrome 6 (MONDO:0032691), Galloway-Mowat syndrome (MONDO:0009627)

Orphanet (1): Galloway-Mowat syndrome (Orphanet:2065)

HPO phenotypes

73 total (30 of 73 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000097	Focal segmental glomerulosclerosis
HP:0000100	Nephrotic syndrome
HP:0000112	Nephropathy
HP:0000154	Wide mouth
HP:0000164	Abnormality of the dentition
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000400	Macrotia
HP:0000463	Anteverted nares
HP:0000520	Proptosis
HP:0000601	Hypotelorism
HP:0000629	Periorbital fullness
HP:0000648	Optic atrophy
HP:0000691	Microdontia
HP:0000733	Motor stereotypy
HP:0000749	Paroxysmal bursts of laughter
HP:0000750	Delayed speech and language development
HP:0000821	Hypothyroidism
HP:0000824	Decreased response to growth hormone stimulation test
HP:0001181	Adducted thumb
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002670_11	Blood and toenail selenium levels	3.000000e-08
GCST004206_16	Fasting plasma glucose	3.000000e-08
GCST004206_7	Fasting plasma glucose	7.000000e-09

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537548	Galloway Mowat syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

60 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
bisphenol A	decreases expression	2
cobaltous chloride	decreases expression, decreases reaction	2
potassium chromate(VI)	affects cotreatment, decreases expression, increases expression	2
chromium hexavalent ion	affects expression, decreases expression, increases abundance	2
Estradiol	affects cotreatment, increases expression	2
Tretinoin	decreases expression	2
Valproic Acid	affects expression, increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
GSK-J4	decreases expression	1
bisphenol F	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
trichostatin A	affects expression	1
afimoxifene	decreases reaction, increases expression	1
zinc chloride	decreases reaction, decreases expression	1
zinc chromate	decreases expression, increases abundance	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
4-phenylbutyric acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
ICG 001	decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
NSC 689534	affects binding, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, increases expression, increases abundance	1
Air Pollutants	increases abundance, increases expression, affects cotreatment	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2LB	Abcam HeLa WDR4 KO	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.