NOMO3

Summary

NOMO3 (NODAL modulator 3, HGNC:25242) is a protein-coding gene on chromosome 16p13.11, encoding BOS complex subunit NOMO3 (P69849). Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes.

This gene encodes a protein originally thought to be related to the collagenase gene family. This gene is one of three highly similar genes in a duplicated region on the short arm of chromosome 16. These three genes encode closely related proteins that may have the same function. The protein encoded by one of these genes has been identified as part of a protein complex that participates in the Nodal signaling pathway during vertebrate development. Mutations in ABCC6, which is located nearby, rather than mutations in this gene are associated with pseudoxanthoma elasticum.

Source: NCBI Gene 408050 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 82 total — 2 likely-pathogenic
• MANE Select transcript: NM_001004067

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25242
Approved symbol	NOMO3
Name	NODAL modulator 3
Location	16p13.11
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000103226
Ensembl biotype	protein_coding
OMIM	609159
Entrez	408050

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 10 protein_coding, 9 nonsense_mediated_decay, 7 retained_intron, 6 protein_coding_CDS_not_defined

ENST00000263012, ENST00000399336, ENST00000570346, ENST00000570519, ENST00000570732, ENST00000571167, ENST00000572033, ENST00000572830, ENST00000572932, ENST00000573635, ENST00000574157, ENST00000574894, ENST00000575225, ENST00000576269, ENST00000576427, ENST00000576460, ENST00000576589, ENST00000676550, ENST00000676846, ENST00000677163, ENST00000677260, ENST00000677777, ENST00000677781, ENST00000677912, ENST00000678080, ENST00000678148, ENST00000678192, ENST00000678393, ENST00000678538, ENST00000679086, ENST00000907104, ENST00000967955

RefSeq mRNA: 1 — MANE Select: NM_001004067 NM_001004067

CCDS: CCDS42123

Canonical transcript exons

ENST00000399336 — 31 exons

Exon	Start	End
ENSE00001607179	16245068	16245174
ENSE00001806303	16294168	16294811
ENSE00002632424	16232528	16232831
ENSE00003469347	16255720	16255825
ENSE00003476066	16280189	16280330
ENSE00003486188	16256008	16256158
ENSE00003490546	16275012	16275171
ENSE00003493928	16293652	16293744
ENSE00003502181	16275317	16275443
ENSE00003513951	16247395	16247467
ENSE00003519468	16252433	16252522
ENSE00003529371	16277370	16277483
ENSE00003545650	16251963	16252100
ENSE00003569901	16239851	16239896
ENSE00003585584	16285405	16285506
ENSE00003588578	16273689	16273907
ENSE00003600750	16270121	16270184
ENSE00003615906	16278662	16278789
ENSE00003622034	16267044	16267131
ENSE00003639403	16250928	16251080
ENSE00003647267	16283016	16283126
ENSE00003647358	16281239	16281322
ENSE00003650211	16265043	16265179
ENSE00003650997	16263513	16263644
ENSE00003656534	16261502	16261676
ENSE00003661090	16243161	16243261
ENSE00003664018	16273993	16274075
ENSE00003667461	16236901	16236990
ENSE00003676914	16263074	16263215
ENSE00003686384	16287743	16287862
ENSE00003692754	16270733	16270828

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 97.04.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2795 / max 10.3185, expressed in 107 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
152964	0.3888	188
207772	0.2795	107

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	97.04	gold quality
pancreas	UBERON:0001264	96.28	gold quality
corpus callosum	UBERON:0002336	96.17	gold quality
islet of Langerhans	UBERON:0000006	95.05	gold quality
nucleus accumbens	UBERON:0001882	93.63	gold quality
right atrium auricular region	UBERON:0006631	93.48	gold quality
bone marrow cell	CL:0002092	93.45	gold quality
adrenal tissue	UBERON:0018303	93.40	gold quality
sural nerve	UBERON:0015488	93.16	gold quality
stromal cell of endometrium	CL:0002255	93.09	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.61	gold quality
cerebellum	UBERON:0002037	92.56	gold quality
cerebellar cortex	UBERON:0002129	92.50	gold quality
cerebellar hemisphere	UBERON:0002245	92.47	gold quality
smooth muscle tissue	UBERON:0001135	92.41	gold quality
muscle tissue	UBERON:0002385	92.39	gold quality
superior frontal gyrus	UBERON:0002661	92.34	gold quality
skeletal muscle tissue	UBERON:0001134	92.12	gold quality
tonsil	UBERON:0002372	92.08	gold quality
monocyte	CL:0000576	91.62	gold quality
leukocyte	CL:0000738	91.58	gold quality
granulocyte	CL:0000094	91.53	gold quality
calcaneal tendon	UBERON:0003701	91.35	gold quality
bone marrow	UBERON:0002371	91.17	gold quality
blood	UBERON:0000178	91.08	gold quality
duodenum	UBERON:0002114	90.98	gold quality
muscle of leg	UBERON:0001383	90.88	gold quality
heart	UBERON:0000948	90.70	gold quality
primary visual cortex	UBERON:0002436	90.66	gold quality
lower esophagus mucosa	UBERON:0035834	90.62	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.50
E-HCAD-5	no	2.28

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

25 targeting NOMO3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-3681-5P	99.82	66.88	387
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-6849-5P	99.64	66.00	352
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-542-3P	99.34	67.58	1270
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-214-3P	98.71	68.12	2128
HSA-MIR-761	98.71	68.07	2051
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-3929	98.32	65.58	1026
HSA-MIR-1245B-3P	98.01	68.91	1387
HSA-MIR-1912-5P	97.94	67.98	832
HSA-MIR-5194	96.77	63.91	1021
HSA-MIR-6508-3P	96.73	65.48	576
HSA-MIR-12115	94.19	66.37	738

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nomo	ENSDARG00000078592
mus_musculus	Nomo1	ENSMUSG00000030835
rattus_norvegicus	Nomo1	ENSRNOG00000021118
drosophila_melanogaster	CG1371	FBGN0033482
caenorhabditis_elegans		WBGENE00015344

Paralogs (2): NOMO1 (ENSG00000103512), NOMO2 (ENSG00000185164)

Protein

Protein identifiers

BOS complex subunit NOMO3 — P69849 (reviewed: P69849)

Alternative names: Nodal modulator 3, pM5 protein 3

All UniProt accessions (14): P69849, A0A7I2V2V8, A0A7I2V2Z5, A0A7I2V3P4, A0A7I2V4D7, A0A7I2V4T6, A0A7I2V686, A0A7I2V6B0, I3L0Q6, I3L1G6, I3L2X2, I3L516, I3NI42, J3KN36

UniProt curated annotations — full annotation on UniProt →

Function. Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes. The MPT complex takes over after the SEC61 complex: following membrane insertion of the first few transmembrane segments of proteins by the SEC61 complex, the MPT complex occludes the lateral gate of the SEC61 complex to promote insertion of subsequent transmembrane regions.

Subunit / interactions. Component of the back of Sec61 (BOS) complex, composed of NCLN/Nicalin, NOMO (NOMO1, NOMO2 or NOMO3) and TMEM147. The BOS complex is part of the multi-pass translocon (MPT) complex, composed of three subcomplexes, the GEL complex (composed of RAB5IF/OPTI and TMCO1), the BOS complex (composed of NCLN/Nicalin, NOMO and TMEM147) and the PAT complex (composed of WDR83OS/Asterix and CCDC47). The MPT complex associates with the SEC61 complex. Due to the strong similarity between NOMO1, NOMO2 and NOMO3, similar interaction pattern probably occur for the three gene copies.

Subcellular location. Endoplasmic reticulum membrane.

RefSeq proteins (1): NP_001004067* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008969	CarboxyPept-like_regulatory	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR013784	Carb-bd-like_fold	Homologous_superfamily
IPR041033	SpaA_PFL_dom_1	Domain
IPR051417	SDr/BOS_complex	Family
IPR055073	NOMO1-like_9th	Domain
IPR055074
IPR055075	NOMO-like_N	Domain
IPR056187	NOMO_8th	Domain
IPR056189	NOMO_3rd	Domain
IPR056190	NOMO_5th	Domain
IPR056191	NOMO_12th	Domain
IPR056319	NOMO_7th	Domain

Pfam: PF13620, PF17802, PF22898, PF22902, PF22904, PF23141, PF23192, PF23193, PF23194, PF23660

UniProt features (12 total): glycosylation site 3, sequence conflict 2, topological domain 2, signal peptide 1, chain 1, transmembrane region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P69849-F1	80.74	0.29

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (3): 50, 218, 618

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 74 (showing top): GOBP_SPECIFICATION_OF_SYMMETRY, GOBP_LATERAL_MESODERM_DEVELOPMENT, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_MEMBRANE, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_ACTIVIN_RECEPTOR_SIGNALING_PATHWAY, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_MESENCHYME_DEVELOPMENT, GOBP_MEMBRANE_ORGANIZATION, GOBP_ENDOPLASMIC_RETICULUM_ORGANIZATION, GOBP_MESODERM_DEVELOPMENT, GOBP_LOCALIZATION_WITHIN_MEMBRANE, GOBP_PROTEIN_INSERTION_INTO_MEMBRANE, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, GOBP_REGULATION_OF_ACTIVIN_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (3): determination of left/right asymmetry in lateral mesoderm (GO:0003140), multi-pass transmembrane protein insertion into ER membrane (GO:0160063), negative regulation of nodal signaling pathway (GO:1900108)

GO Molecular Function (3): carbohydrate binding (GO:0030246), ribosome binding (GO:0043022), protein binding (GO:0005515)

GO Cellular Component (4): endoplasmic reticulum membrane (GO:0005789), multi-pass translocon complex (GO:0160064), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
determination of left/right symmetry	1
lateral mesoderm development	1
protein insertion into ER membrane	1
negative regulation of activin receptor signaling pathway	1
nodal signaling pathway	1
regulation of nodal signaling pathway	1
ribonucleoprotein complex binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
ER membrane insertion complex	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

302 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NOMO3	XYLT1	Q86Y38	918
NOMO3	NCLN	Q969V3	868
NOMO3	SMG1	Q96Q15	762
NOMO3	TMEM147	Q9BVK8	718
NOMO3	DENR	O43583	715
NOMO3	FCF1	Q9Y324	713
NOMO3	MARF1	Q9Y4F3	629
NOMO3	CEP20	Q96NB1	573
NOMO3	TNXB	P22105	571
NOMO3	PACC1	Q9H813	544
NOMO3	ABCC6	P78420	508
NOMO3	PNCK	Q6P2M8	507
NOMO3	SLC9C1	Q4G0N8	506
NOMO3	TNN	Q9UQP3	474
NOMO3	MPV17L	Q2QL34	447

IntAct

46 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
FBXO6	MAN2B1	psi-mi:“MI:0914”(association)	0.640
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
NOMO3	rep	psi-mi:“MI:0915”(physical association)	0.510
NOMO3	GET4	psi-mi:“MI:0915”(physical association)	0.500
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
S100A9	NOMO3	psi-mi:“MI:0915”(physical association)	0.370
TFAP2A	NOMO3	psi-mi:“MI:0915”(physical association)	0.370
TPCN2	DDX11L8	psi-mi:“MI:0914”(association)	0.350
FPR2	GPR89A	psi-mi:“MI:0914”(association)	0.350
ZDHHC5	HACD3	psi-mi:“MI:0914”(association)	0.350
ZDHHC5	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
CCDC47	ESYT2	psi-mi:“MI:0914”(association)	0.350
RBM42	RPS3A	psi-mi:“MI:0914”(association)	0.350
NCLN	PGRMC1	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ST14	LIPT2	psi-mi:“MI:0914”(association)	0.350
TMPRSS13	TOR1A	psi-mi:“MI:0914”(association)	0.350
NOMO3	MAP3K7	psi-mi:“MI:0914”(association)	0.350
SFTPC	TMEM131L	psi-mi:“MI:0914”(association)	0.350
BRICD5	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SDF2L1	MANBA	psi-mi:“MI:0914”(association)	0.350
GGH	MANBA	psi-mi:“MI:0914”(association)	0.350
CBLN4	AGRN	psi-mi:“MI:0914”(association)	0.350
FPR2	SCAMP3	psi-mi:“MI:0914”(association)	0.350
CMKLR1	BTAF1	psi-mi:“MI:0914”(association)	0.350

BioGRID (80): NOMO3 (Affinity Capture-MS), NOMO3 (Proximity Label-MS), NOMO3 (Affinity Capture-MS), NOMO3 (Affinity Capture-MS), NOMO3 (Positive Genetic), NOMO3 (Affinity Capture-MS), NOMO3 (Two-hybrid), NOMO3 (Affinity Capture-MS), NOMO3 (Proximity Label-MS), NOMO3 (Affinity Capture-MS), NOMO3 (Affinity Capture-MS), TAB2 (Affinity Capture-MS), NOMO3 (Affinity Capture-MS), GET4 (Affinity Capture-MS), NOMO1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5PUP4, A2AFS3, M0R7X9, O70472, O75882, O95803, P01134, P26012, P52799, P52848, P69849, Q02353, Q05204, Q0VCJ8, Q12841, Q13635, Q15155, Q3UHN9, Q3ZBS2, Q58D84, Q5EA46, Q5JPE7, Q5R9Y1, Q5U4X8, Q5VV63, Q5ZJB7, Q5ZMH6, Q61115, Q62356, Q62632, Q6A051, Q6GQK9, Q6GQT9, Q6P988, Q6UXG2, Q7Z5A7, Q86TD4, Q90693, Q91WE9, Q96CW9

Diamond homologs: P69849, Q15155, Q5JPE7, Q6GQT9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NOMO3	“form complex”	“BOS complex, NOMO3 variant”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 65 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
ERAD pathway	6	18.8×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	70
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3235906	GRCh38/hg38 16p13.12-13.11(chr16:15032610-16203929)	Likely pathogenic
980075	GRCh37/hg19 16p13.11(chr16:15127985-16527476)x3	Likely pathogenic

SpliceAI

4004 predictions. Top by Δscore:

Variant	Effect	Δscore
16:16232829:GAG:G	donor_gain	1.0000
16:16232831:GGTG:G	donor_loss	1.0000
16:16232832:G:GG	donor_gain	1.0000
16:16232832:GT:G	donor_loss	1.0000
16:16232833:T:G	donor_loss	1.0000
16:16236896:TCCA:T	acceptor_loss	1.0000
16:16236897:CCA:C	acceptor_loss	1.0000
16:16236899:A:AG	acceptor_gain	1.0000
16:16236899:A:T	acceptor_loss	1.0000
16:16236900:G:GG	acceptor_gain	1.0000
16:16236900:G:GT	acceptor_loss	1.0000
16:16236900:GAT:G	acceptor_gain	1.0000
16:16236900:GATA:G	acceptor_gain	1.0000
16:16239846:TTTA:T	acceptor_loss	1.0000
16:16239849:A:AG	acceptor_gain	1.0000
16:16239849:AG:A	acceptor_gain	1.0000
16:16239849:AGG:A	acceptor_gain	1.0000
16:16239849:AGGG:A	acceptor_gain	1.0000
16:16239849:AGGGG:A	acceptor_gain	1.0000
16:16239850:G:GG	acceptor_gain	1.0000
16:16239850:GG:G	acceptor_gain	1.0000
16:16239850:GGG:G	acceptor_gain	1.0000
16:16239850:GGGG:G	acceptor_gain	1.0000
16:16239850:GGGGG:G	acceptor_gain	1.0000
16:16239894:TTGG:T	donor_loss	1.0000
16:16239897:G:GG	donor_gain	1.0000
16:16239897:GTAA:G	donor_loss	1.0000
16:16239898:TAAG:T	donor_loss	1.0000
16:16243133:C:CA	acceptor_gain	1.0000
16:16243146:T:TA	acceptor_gain	1.0000

AlphaMissense

7977 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:16232790:T:C	F42L	1.000
16:16232792:C:A	F42L	1.000
16:16232792:C:G	F42L	1.000
16:16232794:T:A	V43D	1.000
16:16236908:T:C	L58P	1.000
16:16236948:T:G	C71W	1.000
16:16236961:G:C	G76R	1.000
16:16236961:G:T	G76C	1.000
16:16236962:G:A	G76D	1.000
16:16236962:G:T	G76V	1.000
16:16239887:T:A	W98R	1.000
16:16239887:T:C	W98R	1.000
16:16243205:T:A	C116S	1.000
16:16243206:G:C	C116S	1.000
16:16243242:G:A	G128E	1.000
16:16255741:T:C	F329L	1.000
16:16255743:C:A	F329L	1.000
16:16255743:C:G	F329L	1.000
16:16277416:T:C	L897P	1.000
16:16277434:G:C	R903P	1.000
16:16277482:T:C	L919P	1.000
16:16232781:T:A	C39S	0.999
16:16232781:T:C	C39R	0.999
16:16232782:G:A	C39Y	0.999
16:16232782:G:C	C39S	0.999
16:16232787:G:C	G41R	0.999
16:16232788:G:A	G41D	0.999
16:16232791:T:G	F42C	0.999
16:16236946:T:C	C71R	0.999
16:16236947:G:A	C71Y	0.999

dbSNP variants (sampled 300 via entrez): RS1000052553 (16:16269149 C>T), RS1000129157 (16:16267256 A>G), RS1000157373 (16:16232500 G>T), RS1000332914 (16:16242246 C>T), RS1000445255 (16:16232176 C>T), RS1000561677 (16:16255827 T>C), RS1000614211 (16:16256213 A>G), RS1000788898 (16:16242917 C>G), RS1001163702 (16:16234575 A>G), RS1001194364 (16:16272158 A>G), RS1001226203 (16:16233493 G>T), RS1001394648 (16:16245933 T>C), RS1001519629 (16:16259042 T>C), RS1001565101 (16:16260308 G>A), RS1001742952 (16:16245112 G>A)

Disease associations

OMIM: gene MIM:609159 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): 16p13.11 microduplication syndrome (MONDO:0016837)

Orphanet (1): 16p13.11 microduplication syndrome (Orphanet:261243)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression	1
beta-lapachone	decreases expression	1
avobenzone	increases expression	1
bisphenol S	increases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Caffeine	increases phosphorylation	1
Cisplatin	decreases expression	1
Clozapine	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Diethylhexyl Phthalate	increases expression	1
Estradiol	increases expression	1
Ivermectin	decreases expression	1
Selenium	increases expression	1
Testosterone	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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