ELMOD3

Chr 2ADAR

ELMO domain containing 3

Also known as: DFNA81, DFNB88, LST3, RBED1, RBM29

NCBI Gene: 84173 ENSG00000115459 UniProt: Q96FG2 OMIM: 615427

The encoded protein acts as a GTPase-activating protein for ARL2 and is found in cochlear hair cell stereocilia, kinocilia, and cuticular plate during development. Mutations cause autosomal recessive nonsyndromic deafness-88 and possibly autosomal dominant deafness-81. The gene shows very low constraint against loss-of-function variants (pLI near zero), suggesting tolerance to protein loss.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the engulfment and cell motility family of GTPase-activating proteins that regulate Arf GTPase proteins. Members of this family are defined by a conserved engulfment and cell motility domain. In rat cochlea, the encoded protein is found in stereocilia, kinocilia and cuticular plate of developing hair cells suggesting a function for this protein in cochlear sensory cells. An allelic variant of this family has been associated with autosomal recessive nonsyndromic deafness-88 in humans. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 1.612 OMIM phenotypes

Clinical Summary— ELMOD3

🧬

Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ADLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

56 VUS of 100 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?

1.61LOEUF

pLI 0.000

Z-score -0.53

OE 1.13 (0.81–1.61)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.40Z-score

OE missense 0.92 (0.82–1.04)

200 obs / 216.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.13 (0.81–1.61)

0≤0.351.4

Missense OE?0.92 (0.82–1.04)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 22 / 19.5Missense obs/exp: 200 / 216.4Syn Z: 1.00

This gene — mechanism propensity

0.6453th %ile

GOF

0.6638th %ile

LOF

0.3259th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction 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.