ELMOD3

protein-coding

ELMO domain containing 3, the group of RNA binding motif containing|ELMO domain containing

Gene summary

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]

Previous symbols:

RBM29
RBED1
DFNB88

MANE transcript

NM_001135022.2

Inheritance

AR, AD

ClinVar variants

P:1U:94B:49

Top phenotype

Deafness, autosomal recessive 88

gnomAD constraint

pLI —, LoF o/e 1.13

Max pathogenic AF

—

Genomic locus

chr2:85,354,394-85,391,752

External References & Databases

Ensembl (ENSG00000115459)

Transcript & Mutation Effects

hg38 • Region Span ~37.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive nonsyndromic hearing loss 88LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014182

Submitter: Labcorp Genetics (formerly Invitae)

nonsyndromic genetic hearing lossLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: PanelApp Australia

nonsyndromic genetic hearing lossLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: PanelApp Australia

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

nonsyndromic genetic hearing lossLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

ELMOD3 was FIRST reported in relation to autosomal recessive nonsyndromic hearing loss in 2013 (Jaworek et al., PMID: 24039609). At least one homozygous missense variant has been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, expression data, biochemical function data, and a null mouse model. Of note, this gene has also been implicated in autosomal dominant nonsyndromic hearing loss. This has been assessed separately. Summary of Case Level Data: 3 POINTS. Variants in this gene have been reported in at least 1 proband in 1 publication and segregated with disease in 5 additional family members (Jaworek et al., PMID: 24039609). This gene-disease association is supported by expression studies, biochemical function data, and a null mouse model (PMIDs: 31628468, 24039609). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the Hearing Loss GCEP on 5.4.2017. It was reevaluated on 11.17.21 (SOP v 8). Although a new animal model was published (PMID: 31628468), the classification did not change.

autosomal recessive nonsyndromic hearing loss 88LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014182

Submitter: Ambry Genetics

nonsyndromic genetic hearing lossLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

*ELMOD3* was FIRST reported in relation to autosomal dominant nonsyndromic hearing loss in 2018 (Li et al., PMID: 29713870). At least one missense variant has been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and expression data. Of note, this gene has also been implicated in autosomal recessive nonsyndromic hearing loss. This has been assessed separately. Summary of Case Level Data: 0.5 POINTS. Variants in this gene have been reported in at least 1 proband in 1 publication and segregated with disease in 4 additional family members (Li et al., PMID: 29713870). This gene-disease association is supported by expression studies. Of note, the heterozygous *ELMOD3* null mouse does not display a phenotype and was not scored. (Li et al 2019 PMID:31628468). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Hearing Loss Gene Curation Expert Panel on the meeting date 11.17.21 (SOP Version 8).

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 88AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 24039609; 29713870

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ELMOD3 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 148

not specifiedTotal: 76

ELMOD3-related disorderTotal: 14

Hearing loss, autosomal dominant 81Total: 6

Autosomal recessive nonsyndromic hearing loss 88Total: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001135022.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				32 clinvar	2 clinvar	34
missense	1 clinvar		72 clinvar	14 clinvar	1 clinvar	88
nonsense			11 clinvar			11
start loss						0
frameshift			5 clinvar			5
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	1	0	94	46	3	144

Highest pathogenic variant AF is 0.0000034204545

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 132 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001135022.2	RefSeq	NP_001128494.1	11	MANE Select
ENST00000409013.8	Ensembl	ENSP00000387139.3	11	MANE Select
NM_001135021.2	RefSeq	NP_001128493.1	11	Standard
NM_001135023.2	RefSeq	NP_001128495.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

positive regulation of GTPase activity

Molecular Function

GTPase activator activity
protein binding

Cellular Component

cytoplasm
cytoskeleton
stereocilium
kinocilium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000315658
Coding exons: 10
Length: 37359
Individuals with no LoFs: 125643
Homozygous LoFs: 0
Heterozygous LoFs: 105
Defined: 125748
p: 0.000418

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.397	200	216	0.924	0.0000117	2539
Missense (PolyPhen)		63	75.951	0.82948		904
Synonymous	1.00	73	84.7	0.862	0.00000461	777
Loss of Function	-0.527	22	19.5	1.13	0.00000107	208

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00055	0.00055	rare
Latino/Admixed American	0.00081	0.00064	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00054	0.00054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00031	0.00031	rare
South Asian	0.00095	0.00095	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as a GTPase-activating protein (GAP) for ARL2 with low specific activity. {ECO:0000269|PubMed:24039609}.;

Intolerance Scores

LoFtool: 0.999
RVIS EVS: 0.67
RVIS percentile EVS: 84.61

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.300

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium