WDR4

Chr 21AR

WDR4 tRNA N7-guanosine methyltransferase non-catalytic subunit

Also known as: GAMOS6, MIGSB, TRM82, TRMT82, Wuho, hWH

NCBI Gene: 10785 ENSG00000160193 UniProt: P57081 OMIM: 605924

WDR4 encodes a non-catalytic component of the METTL1-WDR4 methyltransferase complex that acts as a scaffold for tRNA binding and is required for N(7)-methylguanine formation in tRNAs, mRNAs, and microRNAs. Mutations cause autosomal recessive Galloway-Mowat syndrome 6 and a distinct phenotype of microcephaly, growth deficiency, seizures, and brain malformations. The gene is highly constrained against loss-of-function variants (LOEUF 1.116), consistent with severe developmental phenotypes when disrupted.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.122 OMIM phenotypes

Clinical Summary— WDR4

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

20 unique Pathogenic / Likely Pathogenic· 138 VUS of 359 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.12LOEUF

pLI 0.000

Z-score 1.16

OE 0.72 (0.48–1.12)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.02Z-score

OE missense 1.18 (1.07–1.30)

304 obs / 257.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.72 (0.48–1.12)

0≤0.351.4

Missense OE?1.18 (1.07–1.30)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 15 / 20.7Missense obs/exp: 304 / 257.9Syn Z: -1.47

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedWDR4-related Galloway-Mowat syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6357th %ile

GOF

0.4875th %ile

LOF

0.3842th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

359 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11

Likely Pathogenic9

VUS138

Likely Benign136

Benign38

Conflicting6

Pathogenic

Likely Pathogenic

138

VUS

136

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	8	1	2	0	11
Likely Pathogenic	4	4	1	0	9
VUS	2	128	8	0	138
Likely Benign	2	13	49	72	136
Benign	0	3	29	6	38
Conflicting	—				6
Total	16	149	89	78	338

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

85 pathogenic / likely-pathogenic (of 96) ClinVar copy-number / structural variants overlap WDR4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →