WHAMM

Chr 15

WASP homolog associated with actin, golgi membranes and microtubules

Also known as: WHAMM1, WHDC1

NCBI Gene: 123720 ENSG00000156232 UniProt: Q8TF30 OMIM: 612393

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.

OMIM 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]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 1.15

Clinical Summary— WHAMM

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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

137 VUS of 152 total submissions

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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

This gene — mechanism propensity

0.5673th %ile

GOF

0.6540th %ile

LOF

0.4430th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

152 submitted variants in ClinVar

ClinVar

Classification Summary

VUS137

Likely Benign7

Benign2

137

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	137	0	137
Likely Benign	6	1	7
Benign	1	1	2
Total	144	2	146

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

View in ClinVar →

33 pathogenic / likely-pathogenic (of 40) ClinVar copy-number / structural variants overlap WHAMM — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →