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…

Primary Disease Associations & Inheritance

Galloway-Mowat syndrome 6MIM #618347

Microcephaly, growth deficiency, seizures, and brain malformationsMIM #618346

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Galloway-Mowat syndrome 6; Microcephaly, growth deficiency, seizures, and brain malformations; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.12

LOEUF

LOF

Mechanism· G2P

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

Background carrier burden — how many people carry a rare variant somewhere in WDR4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 61

657 rare PASS variants

Rare truncating (LoF)

1 in 480

121 rare PASS variants

Rare synonymous (reference)

1 in 120

281 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for WDR4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 89	1 in 2,000
South Asian	~43k	1 in 50	1 in 2,600
Remaining (unassigned)	~30k	1 in 55	1 in 990
European (Finnish)	~27k	1 in 200	1 in 2,700
Admixed American	~22k	1 in 57	1 in 1,600
African / African American	~21k	1 in 53	1 in 1,900
East Asian	~20k	1 in 64	1 in 1,600
Ashkenazi Jewish	~13k	1 in 340	1 in 1,000
Middle Eastern	~2,884	1 in 110	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 11 coding exons well covered in gnomAD exomes and genomes.? see exons ↓