ELMOD3

Summary

ELMOD3 (ELMO domain containing 3, HGNC:26158) is a protein-coding gene on chromosome 2p11.2, encoding ELMO domain-containing protein 3 (Q96FG2). Acts as a GTPase-activating protein (GAP) for ARL2 with low specific activity.

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.

Source: NCBI Gene 84173 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hearing loss, autosomal recessive (Supportive, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 233 total — 1 pathogenic
• Phenotypes (HPO): 6
• MANE Select transcript: NM_001135022

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26158
Approved symbol	ELMOD3
Name	ELMO domain containing 3
Location	2p11.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ21977
Ensembl gene	ENSG00000115459
Ensembl biotype	protein_coding
OMIM	615427
Entrez	84173

Gene structure

Transcript identifiers

Ensembl transcripts: 47 — 33 protein_coding, 7 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000315658, ENST00000393852, ENST00000409013, ENST00000409331, ENST00000409344, ENST00000409890, ENST00000410106, ENST00000414593, ENST00000418268, ENST00000423095, ENST00000429764, ENST00000440462, ENST00000444108, ENST00000446464, ENST00000462396, ENST00000462891, ENST00000466467, ENST00000476734, ENST00000486908, ENST00000488150, ENST00000490508, ENST00000496957, ENST00000893328, ENST00000893329, ENST00000893330, ENST00000893331, ENST00000893332, ENST00000893333, ENST00000893334, ENST00000893335, ENST00000893336, ENST00000893337, ENST00000893338, ENST00000893339, ENST00000893340, ENST00000893341, ENST00000930904, ENST00000956633, ENST00000956634, ENST00000956635, ENST00000956636, ENST00000956637, ENST00000956638, ENST00000956639, ENST00000956640, ENST00000956641, ENST00000956642

RefSeq mRNA: 7 — MANE Select: NM_001135022 NM_001135021, NM_001135022, NM_001135023, NM_001329791, NM_001329792, NM_001329793, NM_032213

CCDS: CCDS1973, CCDS46352

Canonical transcript exons

ENST00000409013 — 14 exons

Exon	Start	End
ENSE00001516745	85355076	85355170
ENSE00001585141	85354769	85354829
ENSE00001587812	85355555	85355598
ENSE00001723346	85390760	85391748
ENSE00003459868	85362186	85362260
ENSE00003493765	85371086	85371209
ENSE00003509903	85363097	85363166
ENSE00003541817	85371440	85371562
ENSE00003547945	85356967	85357252
ENSE00003573981	85377344	85377474
ENSE00003600129	85390138	85390265
ENSE00003634838	85368686	85368754
ENSE00003684817	85389751	85389827
ENSE00003787146	85369739	85369830

Expression profiles

Bgee: expression breadth ubiquitous, 190 present calls, max score 94.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.9915 / max 93.4028, expressed in 1763 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21205	7.7739	1762
21207	0.2176	32

Top tissues by expression

244 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
subcutaneous adipose tissue	UBERON:0002190	94.23	gold quality
adipose tissue	UBERON:0001013	92.96	gold quality
omental fat pad	UBERON:0010414	92.88	gold quality
peritoneum	UBERON:0002358	92.81	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.81	gold quality
granulocyte	CL:0000094	91.70	gold quality
right lobe of thyroid gland	UBERON:0001119	90.72	gold quality
left lobe of thyroid gland	UBERON:0001120	90.54	gold quality
right adrenal gland cortex	UBERON:0035827	90.31	gold quality
gastrocnemius	UBERON:0001388	90.15	gold quality
right adrenal gland	UBERON:0001233	90.03	gold quality
muscle of leg	UBERON:0001383	89.55	gold quality
lower esophagus mucosa	UBERON:0035834	89.43	gold quality
left adrenal gland cortex	UBERON:0035825	89.42	gold quality
thyroid gland	UBERON:0002046	89.36	gold quality
left coronary artery	UBERON:0001626	89.29	gold quality
left adrenal gland	UBERON:0001234	89.26	gold quality
nerve	UBERON:0001021	89.14	gold quality
tibial nerve	UBERON:0001323	89.14	gold quality
popliteal artery	UBERON:0002250	89.03	gold quality
tibial artery	UBERON:0007610	89.03	gold quality
endocervix	UBERON:0000458	89.00	gold quality
skin of leg	UBERON:0001511	89.00	gold quality
mucosa of transverse colon	UBERON:0004991	88.90	gold quality
body of stomach	UBERON:0001161	88.86	gold quality
cerebellar hemisphere	UBERON:0002245	88.84	gold quality
artery	UBERON:0001637	88.79	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.79	gold quality
right ovary	UBERON:0002118	88.77	gold quality
cerebellar cortex	UBERON:0002129	88.68	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.18

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 5)

• Collectively, our data provide the first insights into the expression and biochemical properties of ELMOD3 and highlight its functional links to sound perception and actin cytoskeleton. (PMID:24039609)
• The non-opioid sigma-1 receptor (S1R) was identified as a novel effector of GAP activity of ELMOD1-3 proteins as its direct binding to either ELMOD1 or ELMOD2 resulted in loss of GAP activity. (PMID:24616099)
• the analysis of the stability of the wild-type (WT) and mutant ELMOD3 protein shows that the decay of p.His171Arg is faster than that of the WT, suggesting a shorter halflife of the c.512A > G variant. A novel variant in the ELMOD3 gene, encoding a member of the engulfment and cell motility (ELMO) family (PMID:29713870)
• ELMOD3-SH2D6 gene fusion as a possible co-star actor in autism spectrum disorder scenario. (PMID:31800155)
• Gene regulation analysis of patient-derived iPSCs and its CRISPR-corrected control provides a new tool for studying perturbations of ELMOD3 c.512A>G mutation during the development of inherited hearing loss. (PMID:37708136)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	elmod3	ENSDARG00000074742
mus_musculus	Elmod3	ENSMUSG00000056698
rattus_norvegicus	Elmod3	ENSRNOG00000038102
caenorhabditis_elegans		WBGENE00008348

Paralogs (5): ELMO2 (ENSG00000062598), ELMO3 (ENSG00000102890), ELMOD1 (ENSG00000110675), ELMO1 (ENSG00000155849), ELMOD2 (ENSG00000179387)

Protein

Protein identifiers

ELMO domain-containing protein 3 — Q96FG2 (reviewed: Q96FG2)

Alternative names: RNA-binding motif and ELMO domain-containing protein 1, RNA-binding motif protein 29, RNA-binding protein 29

All UniProt accessions (7): B8ZZT8, D3YTJ5, D6R929, D6RHZ3, E9PI96, Q96FG2, F8WEC1

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a GTPase-activating protein (GAP) for ARL2 with low specific activity.

Subcellular location. Cell projection. Stereocilium. Kinocilium. Cytoplasm. Cytoskeleton.

Tissue specificity. Both isoform 1 and isoform 6 are widely expressed.

Disease relevance. Deafness, autosomal recessive, 88 (DFNB88) [MIM:615429] A form of non-syndromic deafness characterized by prelingual onset of severe to profound mixed conductive and sensorineural hearing loss. The disease may be caused by variants affecting the gene represented in this entry. Deafness, autosomal dominant, 81 (DFNA81) [MIM:619500] A form of non-syndromic, sensorineural hearing loss. Sensorineural hearing loss results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DNFA81 is characterized by postlingual onset of slowly progressive deafness. The disease may be caused by variants affecting the gene represented in this entry.

Isoforms (5)

UniProt ID	Names	Canonical?
Q96FG2-1	1, B/C/D	yes
Q96FG2-2	2
Q96FG2-3	3
Q96FG2-5	5
Q96FG2-6	6, A

RefSeq proteins (7): NP_001128493, NP_001128494, NP_001128495, NP_001316720, NP_001316721, NP_001316722, NP_115589 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006816	ELMO_dom	Domain
IPR050868	ELMO_domain-containing	Family

Pfam: PF04727

UniProt features (18 total): splice variant 6, sequence variant 4, sequence conflict 4, chain 1, domain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96FG2-F1	76.18	0.54

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 139 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_CELLULAR_COMPONENT_MAINTENANCE, GOBP_NEUROGENESIS, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, GERY_CEBP_TARGETS, GOBP_EAR_DEVELOPMENT, GOBP_CILIUM_ORGANIZATION, AAAGGGA_MIR204_MIR211, GOBP_ORGANELLE_ASSEMBLY, GOBP_EPIDERMIS_DEVELOPMENT, GOBP_AUDITORY_RECEPTOR_CELL_DEVELOPMENT, GOBP_MECHANORECEPTOR_DIFFERENTIATION, GOBP_HAIR_CELL_DIFFERENTIATION, GOBP_SENSORY_PERCEPTION

GO Biological Process (8): cytoskeleton organization (GO:0007010), sensory perception of sound (GO:0007605), gene expression (GO:0010467), protein transport (GO:0015031), auditory receptor cell development (GO:0060117), cilium assembly (GO:0060271), stereocilium maintenance (GO:0120045), intracellular protein localization (GO:0008104)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (7): Golgi apparatus (GO:0005794), cytoskeleton (GO:0005856), stereocilium (GO:0032420), kinocilium (GO:0060091), cytoplasm (GO:0005737), cilium (GO:0005929), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
stereocilium bundle	2
neuron projection	2
cellular anatomical structure	2
organelle organization	1
sensory perception of mechanical stimulus	1
macromolecule biosynthetic process	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
inner ear auditory receptor cell differentiation	1
inner ear receptor cell development	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
cellular component maintenance	1
inner ear receptor cell stereocilium organization	1
macromolecule localization	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
actin-based cell projection	1
radial spoke	1
organelle	1
9+2 non-motile cilium	1
intracellular anatomical structure	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

574 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ELMOD3	ELMOD1	Q8N336	791
ELMOD3	SH2D6	Q7Z4S9	695
ELMOD3	ARL2	P36404	546
ELMOD3	ELMO3	Q96BJ8	515
ELMOD3	RASA1	P20936	504
ELMOD3	ELMO1	Q92556	495
ELMOD3	ELMO2	Q96JJ3	490
ELMOD3	ARL3	P36405	435
ELMOD3	ELMOD2	Q8IZ81	432
ELMOD3	ARMC8	Q8IUR7	417
ELMOD3	RETSAT	Q6NUM9	401
ELMOD3	CYTH2	Q99418	397
ELMOD3	IMMP1L	Q96LU5	394
ELMOD3	C2orf68	Q2NKX9	392
ELMOD3	ARHGAP39	Q9C0H5	387

IntAct

6 interactions, top by confidence:

A	B	Type	Score
MAGEA6	ELMOD3	psi-mi:“MI:0915”(physical association)	0.560
ELMOD3	MAGEA6	psi-mi:“MI:0915”(physical association)	0.560
ELMOD3	DDI2	psi-mi:“MI:0914”(association)	0.350
CDH1	ESYT2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (18): ELMOD3 (Two-hybrid), ASPRV1 (Affinity Capture-MS), S100A7 (Affinity Capture-MS), ELMOD3 (Proximity Label-MS), ASPRV1 (Affinity Capture-MS), ELMOD3 (Proximity Label-MS), ELMOD3 (Proximity Label-MS), ELMOD3 (Proximity Label-MS), ELMOD3 (Synthetic Lethality), ELMOD3 (Affinity Capture-RNA), ELMOD3 (Positive Genetic), ELMOD3 (Affinity Capture-RNA), ELMOD3 (Proximity Label-MS), DDI2 (Affinity Capture-MS), MAP1S (Affinity Capture-MS)

ESM2 similar proteins: A0A494C1R9, A2AKB4, A2APT9, A6NKD2, A8MT33, B0BN44, E9PGG2, F5GYI3, O19110, O88852, P0CV98, P0CV99, P0CW00, P0CW01, Q01534, Q03386, Q0P5N2, Q12967, Q14684, Q2M329, Q3U3N0, Q5F267, Q5I0E2, Q5R5G8, Q5R866, Q5SYB0, Q5VTJ3, Q60953, Q69ZB3, Q6ZUX3, Q7TQI8, Q80VJ8, Q80VR2, Q86VY4, Q8BSI6, Q8IZJ4, Q8N831, Q8VD63, Q95LS7, Q96FG2

Diamond homologs: Q58DT5, Q5XIQ2, Q91YP6, Q96FG2, Q5NVD7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

233 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	104
Likely benign	72
Benign	32

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
65464	NM_001135022.2(ELMOD3):c.794T>C (p.Leu265Ser)	Pathogenic

SpliceAI

2168 predictions. Top by Δscore:

Variant	Effect	Δscore
2:85357044:G:T	donor_gain	1.0000
2:85362180:TTACA:T	acceptor_loss	1.0000
2:85362181:TACAG:T	acceptor_loss	1.0000
2:85362183:CA:C	acceptor_loss	1.0000
2:85362184:AG:A	acceptor_gain	1.0000
2:85362185:GG:G	acceptor_gain	1.0000
2:85362185:GGGT:G	acceptor_gain	1.0000
2:85362261:G:GG	donor_gain	1.0000
2:85368684:A:AG	acceptor_gain	1.0000
2:85368685:G:GG	acceptor_gain	1.0000
2:85371176:G:GT	donor_gain	1.0000
2:85371208:GT:G	donor_gain	1.0000
2:85377471:CCAGG:C	donor_loss	1.0000
2:85377473:AGG:A	donor_loss	1.0000
2:85377475:G:T	donor_loss	1.0000
2:85377476:T:A	donor_loss	1.0000
2:85390133:TGCA:T	acceptor_loss	1.0000
2:85390134:GCAG:G	acceptor_loss	1.0000
2:85390135:CAGAG:C	acceptor_gain	1.0000
2:85390136:A:AG	acceptor_gain	1.0000
2:85390136:AGAG:A	acceptor_loss	1.0000
2:85390136:AGAGA:A	acceptor_gain	1.0000
2:85390137:G:GT	acceptor_gain	1.0000
2:85390137:GA:G	acceptor_gain	1.0000
2:85390137:GAGA:G	acceptor_gain	1.0000
2:85390137:GAGAG:G	acceptor_gain	1.0000
2:85390231:G:GT	donor_gain	1.0000
2:85390261:CAAAG:C	donor_loss	1.0000
2:85390262:AAAG:A	donor_loss	1.0000
2:85390263:AAGG:A	donor_loss	1.0000

AlphaMissense

2472 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:85371556:T:C	F201L	0.995
2:85371557:T:C	F201S	0.995
2:85371558:T:A	F201L	0.995
2:85371558:T:G	F201L	0.995
2:85371543:G:C	W196C	0.992
2:85371543:G:T	W196C	0.992
2:85371541:T:A	W196R	0.990
2:85371541:T:C	W196R	0.990
2:85389754:T:C	F248L	0.986
2:85389756:C:A	F248L	0.986
2:85389756:C:G	F248L	0.986
2:85390217:T:A	W299R	0.985
2:85390217:T:C	W299R	0.985
2:85371500:T:C	L182P	0.979
2:85389763:T:C	C251R	0.979
2:85371557:T:G	F201C	0.978
2:85371542:G:C	W196S	0.977
2:85371553:G:C	G200R	0.977
2:85389755:T:C	F248S	0.976
2:85371556:T:G	F201V	0.975
2:85390190:G:C	A290P	0.975
2:85389785:C:T	T258I	0.973
2:85371192:T:A	V156D	0.972
2:85390142:T:C	C274R	0.972
2:85371204:C:A	A160D	0.969
2:85377377:G:A	G214D	0.969
2:85371554:G:T	G200V	0.968
2:85390206:T:C	L295P	0.968
2:85389755:T:G	F248C	0.967
2:85390219:G:C	W299C	0.966

dbSNP variants (sampled 300 via entrez): RS1000018937 (2:85382205 C>G,T), RS1000028798 (2:85367268 C>T), RS1000088707 (2:85382488 G>C), RS1000143009 (2:85367000 G>T), RS1000166133 (2:85364994 T>A,C), RS1000268610 (2:85357857 T>C), RS1000281400 (2:85391756 T>C), RS1000369455 (2:85389240 A>G), RS1000374238 (2:85360400 C>T), RS1000542568 (2:85379124 C>T), RS1000621598 (2:85364381 C>G,T), RS1000624527 (2:85385276 A>G), RS1000657170 (2:85378827 C>T), RS1000775390 (2:85385601 C>G,T), RS1000978121 (2:85390755 T>TG,TGG)

Disease associations

OMIM: gene MIM:615427 | disease phenotypes: MIM:619500, MIM:615429

GenCC curated gene-disease

Disease	Classification	Inheritance
hearing loss, autosomal recessive	Supportive	Autosomal recessive
autosomal recessive nonsyndromic hearing loss 88	Limited	Autosomal recessive
nonsyndromic genetic hearing loss	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Limited	AD
nonsyndromic genetic hearing loss	Limited	AR

Mondo (4): hearing loss, autosomal dominant 81 (MONDO:0030549), autosomal recessive nonsyndromic hearing loss 88 (MONDO:0014182), nonsyndromic genetic hearing loss (MONDO:0019497), hearing loss, autosomal recessive (MONDO:0019588)

Orphanet (1): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636)

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000410	Mixed hearing impairment
HP:0001751	Abnormal vestibular function
HP:0011462	Young adult onset

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C564609	Deafness, Autosomal Recessive (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
sodium arsenite	affects expression	1
2-palmitoylglycerol	increases expression	1
jinfukang	increases expression	1
Leflunomide	decreases expression	1
Acetaminophen	increases expression	1
Atrazine	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression	1
Gallic Acid	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	increases expression	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

1 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations