WHAMM

Chr 15

WASP homolog associated with actin, golgi membranes and microtubules

Also known as: WHAMM1, WHDC1

NCBI Gene: 123720 ENSG00000156232 UniProt: Q8TF30

This gene encodes a nucleation-promoting factor that stimulates actin polymerization at the Golgi apparatus and regulates vesicle transport between the endoplasmic reticulum and Golgi complex through coordinated actin and microtubule interactions. Mutations cause microcephaly with seizures and developmental delay, inherited in an autosomal recessive pattern. The gene shows no constraint against loss-of-function variants, consistent with the recessive inheritance pattern observed in affected individuals.

ResearchSummary from RefSeq, UniProt

This gene encodes a protein that plays a role in actin nucleation, Golgi membrane association and microtubule binding. The encoded protein is a nucleation-promoting factor that regulates the Actin-related protein 2/3 complex. The activated complex initiates growth of new actin filaments by binding to existing actin filaments. The encoded protein also functions in regulation of transport from the endoplasmic reticulum to the Golgi complex and in maintenance of the Golgi complex near the centrosome. Four pseudogenes of this gene are present on the same arm of chromosome 15 as this gene. [provided by RefSeq, Aug 2013]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.15

LOEUF

GOF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.15LOEUF

pLI 0.000

Z-score 0.93

OE 0.81 (0.58–1.15)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.18Z-score

OE missense 1.03 (0.94–1.12)

367 obs / 357.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.81 (0.58–1.15)

0≤0.351.4

Missense OE?1.03 (0.94–1.12)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 22 / 27.2Missense obs/exp: 367 / 357.4Syn Z: -1.40

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 48

1,127 rare PASS variants

Rare truncating (LoF)

1 in 270

210 rare PASS variants

Rare synonymous (reference)

1 in 140

443 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for WHAMM. 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 65	1 in 540
South Asian	~43k	1 in 40	1 in 200
Remaining (unassigned)	~30k	1 in 39	1 in 330
European (Finnish)	~27k	1 in 170	1 in 940
Admixed American	~22k	1 in 42	1 in 320
African / African American	~21k	1 in 43	1 in 550
East Asian	~20k	1 in 41	1 in 660
Ashkenazi Jewish	~13k	1 in 200	1 in 1,500
Middle Eastern	~2,884	1 in 38	≈ 1 in 580

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): 7 of 10 coding exons well covered in gnomAD exomes; exon 5 poorly covered; exons 1, 6 marginal. Genomes: all 10.? see exons ↓