TOM1

Summary

TOM1 (target of myb1 membrane trafficking protein, HGNC:11982) is a protein-coding gene on chromosome 22q12.3, encoding Target of Myb1 membrane trafficking protein (O60784). Adapter protein that plays a role in the intracellular membrane trafficking of ubiquitinated proteins, thereby participating in autophagy, ubiquitination-dependent signaling and receptor recycling pathways.

This gene was identified as a target of the v-myb oncogene. The encoded protein shares its N-terminal domain in common with proteins associated with vesicular trafficking at the endosome. It is recruited to the endosomes by its interaction with endofin. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10043 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immune system disorder (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 18
• Clinical variants (ClinVar): 104 total — 1 pathogenic
• Phenotypes (HPO): 24
• MANE Select transcript: NM_005488

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11982
Approved symbol	TOM1
Name	target of myb1 membrane trafficking protein
Location	22q12.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000100284
Ensembl biotype	protein_coding
OMIM	604700
Entrez	10043

Gene structure

Transcript identifiers

Ensembl transcripts: 41 — 31 protein_coding, 5 nonsense_mediated_decay, 5 retained_intron

ENST00000395736, ENST00000404284, ENST00000411850, ENST00000424387, ENST00000425375, ENST00000439512, ENST00000443206, ENST00000447733, ENST00000449058, ENST00000449508, ENST00000456128, ENST00000465529, ENST00000487670, ENST00000491987, ENST00000492723, ENST00000497448, ENST00000608674, ENST00000608749, ENST00000883940, ENST00000883941, ENST00000883942, ENST00000883943, ENST00000883944, ENST00000883945, ENST00000883946, ENST00000883947, ENST00000883948, ENST00000883949, ENST00000883950, ENST00000883951, ENST00000883952, ENST00000929704, ENST00000953245, ENST00000953246, ENST00000953247, ENST00000953248, ENST00000953249, ENST00000953250, ENST00000953251, ENST00000953252, ENST00000953253

RefSeq mRNA: 4 — MANE Select: NM_005488 NM_001135729, NM_001135730, NM_001135732, NM_005488

CCDS: CCDS13913, CCDS46696, CCDS46697, CCDS46698

Canonical transcript exons

ENST00000449058 — 15 exons

Exon	Start	End
ENSE00001845511	35347055	35347973
ENSE00003459618	35332981	35333014
ENSE00003470333	35327271	35327387
ENSE00003562438	35330347	35330480
ENSE00003597398	35317877	35317961
ENSE00003599867	35338713	35338788
ENSE00003601393	35299894	35299980
ENSE00003603407	35334328	35334448
ENSE00003635588	35323028	35323177
ENSE00003638172	35345725	35345784
ENSE00003652536	35333404	35333497
ENSE00003680771	35346930	35346969
ENSE00003715408	35323768	35323914
ENSE00003740916	35321959	35322037
ENSE00003790202	35323496	35323630

Expression profiles

Bgee: expression breadth ubiquitous, 207 present calls, max score 97.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 59.9591 / max 1524.8431, expressed in 1826 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191957	51.9045	1826
191958	4.4330	391
191980	1.4319	382
191981	1.2081	344
191979	0.6660	212
191961	0.3156	128

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	97.93	gold quality
gastrocnemius	UBERON:0001388	97.83	gold quality
muscle of leg	UBERON:0001383	97.31	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.17	gold quality
skin of leg	UBERON:0001511	96.71	gold quality
skin of abdomen	UBERON:0001416	95.91	gold quality
monocyte	CL:0000576	95.87	gold quality
apex of heart	UBERON:0002098	95.86	gold quality
stromal cell of endometrium	CL:0002255	95.71	gold quality
minor salivary gland	UBERON:0001830	95.65	gold quality
esophagus mucosa	UBERON:0002469	95.46	gold quality
left adrenal gland	UBERON:0001234	95.33	gold quality
left adrenal gland cortex	UBERON:0035825	95.23	gold quality
right adrenal gland cortex	UBERON:0035827	95.12	gold quality
right adrenal gland	UBERON:0001233	95.10	gold quality
mononuclear cell	CL:0000842	95.09	gold quality
leukocyte	CL:0000738	94.90	gold quality
right lobe of liver	UBERON:0001114	94.83	gold quality
adenohypophysis	UBERON:0002196	94.37	gold quality
upper lobe of left lung	UBERON:0008952	94.19	gold quality
right lung	UBERON:0002167	94.12	gold quality
ectocervix	UBERON:0012249	94.03	gold quality
granulocyte	CL:0000094	93.86	gold quality
right atrium auricular region	UBERON:0006631	93.72	gold quality
islet of Langerhans	UBERON:0000006	93.57	gold quality
gall bladder	UBERON:0002110	93.56	gold quality
saliva-secreting gland	UBERON:0001044	93.41	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.41	gold quality
muscle organ	UBERON:0001630	93.35	gold quality
adrenal gland	UBERON:0002369	93.16	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-106540	yes	532.29
E-ANND-3	yes	13.85
E-MTAB-7249	no	594.53
E-MTAB-6058	no	34.19

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPG, CREB1, ETS1, GLI1, MYB, MYBL2

miRNA regulators (miRDB)

34 targeting TOM1, 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-4455	100.00	65.48	1587
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-324-3P	99.26	66.31	1034
HSA-MIR-122B-3P	99.21	68.90	1333
HSA-MIR-21-3P	99.21	68.95	1312
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-1207-3P	98.99	66.22	1532
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-7851-3P	98.72	64.88	980
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-6810-5P	98.29	66.21	975
HSA-MIR-12120	98.05	68.44	1768
HSA-MIR-6847-5P	97.93	66.74	1808
HSA-MIR-450A-2-3P	97.91	67.56	1459
HSA-MIR-4660	97.79	67.44	1328
HSA-MIR-296-5P	97.61	64.02	851

Literature-anchored findings (GeneRIF, showing 12)

• a Tom1-Tollip complex functions as a factor that links polyubiquitinated proteins to clathrin (PMID:14563850)
• marked recruitment of TOM1 to endosomes was observed in cells overexpressing endofin or its carboxyl-terminal fragment (PMID:14613930)
• Tollip and Tom1 form a complex and regulate endosomal trafficking of ubiquitinated proteins (PMID:15047686)
• The results suggest that TOM1 is an important molecule for membrane recruitment of clathrin, and that endofin is able to exploit this recruitment at the endosome. (PMID:15657082)
• A 3-marker haplotype of SNPs within TOM1 was associated with psychotic bipolar affective disorder linkage (PMID:17671966)
• TOM1 is a microRNA-126 target that may have an important role in regulating innate immune responses in the cystic fibrosis lung. (PMID:20083669)
• It was shown that that myosin VI, in concert with Tom1, plays a crucial role in autophagy. Tom1 was identified as a myosin VI binding partner on endosomes. (PMID:23023224)
• phosphatidylinositol 5-monophosphate (PI5P) enrichment in signaling endosomes prevents endosomal maturation through the recruitment of TOM1, and point to a new function of PI5P in regulating discrete maturation steps in the endosomal system. (PMID:25588840)
• candidate multiple myeloma risk locus (PMID:26007630)
• Tom1 modulates binding of Tollip to phosphatidylinositol 3-phosphate via a coupled folding and binding mechanism. (PMID:26320582)
• This study demonstrated that Tom1 is localized in dystrophic neurites of brain in patient with Alzheimer’s disease. (PMID:27206884)
• Study shows that TOM1 regulates neuronal accumulation of amyloid-beta oligomers by FcgammaRIIb2 variant in Alzheimer’s Disease (AD). Study provides a molecular mechanism responsible for neuronal uptake of pathogenic Abeta found in AD. (PMID:30185465)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	tom1	ENSDARG00000104581
mus_musculus	Tom1	ENSMUSG00000042870
rattus_norvegicus	Tom1	ENSRNOG00000014093
drosophila_melanogaster	Stam	FBGN0027363
drosophila_melanogaster	Gga	FBGN0030141
drosophila_melanogaster	Wdfy2	FBGN0032246
drosophila_melanogaster	CG3529	FBGN0035995
caenorhabditis_elegans	stam-1	WBGENE00004109
caenorhabditis_elegans		WBGENE00008402
caenorhabditis_elegans		WBGENE00015561

Paralogs (10): WDFY1 (ENSG00000085449), GGA1 (ENSG00000100083), GGA2 (ENSG00000103365), STAM2 (ENSG00000115145), GGA3 (ENSG00000125447), STAM (ENSG00000136738), WDFY2 (ENSG00000139668), TOM1L1 (ENSG00000141198), TOM1L2 (ENSG00000175662), HGS (ENSG00000185359)

Protein

Protein identifiers

Target of Myb1 membrane trafficking protein — O60784 (reviewed: O60784)

Alternative names: Target of Myb protein 1

All UniProt accessions (10): O60784, B0QY01, B0QY02, F8WAW7, F8WB30, F8WBB0, F8WE29, H7BYN7, V9GYF4, V9GZ68

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein that plays a role in the intracellular membrane trafficking of ubiquitinated proteins, thereby participating in autophagy, ubiquitination-dependent signaling and receptor recycling pathways. Acts as a MYO6/Myosin VI adapter protein that targets MYO6 to endocytic structures. Together with MYO6, required for autophagosomal delivery of endocytic cargo, the maturation of autophagosomes and their fusion with lysosomes. MYO6 links TOM1 with autophagy receptors, such as TAX1BP1; CALCOCO2/NDP52 and OPTN. Binds to polyubiquitinated proteins via its GAT domain. In a complex with TOLLIP, recruits ubiquitin-conjugated proteins onto early endosomes. The Tom1-Tollip complex may regulate endosomal trafficking by linking polyubiquitinated proteins to clathrin. Mediates clathrin recruitment to early endosomes by ZFYVE16. Modulates binding of TOLLIP to phosphatidylinositol 3-phosphate (PtdIns(3)P) via binding competition; the association with TOLLIP may favor the release of TOLLIP from endosomal membranes, allowing TOLLIP to commit to cargo trafficking. Acts as a phosphatidylinositol 5-phosphate (PtdIns(5)P) effector by binding to PtdIns(5)P, thereby regulating endosomal maturation. PtdIns(5)P-dependent recruitment to signaling endosomes may block endosomal maturation. Also inhibits Toll-like receptor (TLR) signaling and participates in immune receptor recycling.

Subunit / interactions. Found in a complex with TOLLIP; interacts (via GAT domain) with TOLLIP (via N-terminus); the interactions leads to TOM1-recruitment to endosomes and inhibition of TOLLIP binding to PtdIns(3)P. Interacts (via GAT domain and the C-terminal part of the VHS domain) with UBC/ubiquitin. Interacts (via clathrin box and C-terminus) with clathrin heavy chain. Interacts with MYO6. Interacts with TAX1BP1; CALCOCO2/NDP52 and OPTN; the interaction is indirect and is mediated by MYO6, which acts as a bridge between TOM1 and the three autophagy receptors. Interacts (via C-terminus) with ZFYVE16 (via C-terminus); interaction is required to target TOM1 and clathrin to endosomes. Interacts with LRBA.

Subcellular location. Cytoplasm. Endosome membrane. Early endosome membrane.

Tissue specificity. Widely expressed. Highly expressed in skeletal muscle, heart, placenta and liver.

Post-translational modifications. Monoubiquitinated.

Disease relevance. Immunodeficiency 85 (IMD85) [MIM:619510] An autosomal dominant immunologic disorder characterized by early-onset autoimmunity and features of combined immunodeficiency such as hypogammaglobulinemia and abnormal T-cell function. Clinical manifestations include atopic eczema and recurrent respiratory infections in the first decade of life, autoimmune enteropathy, growth failure, autoimmune oligoarthritis, interstitial pneumonitis, and EBV viremia. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Domain organisation. The GAT domain and the VHS domain are required for the interaction with polyubiquitinated proteins. The VHS domain binds to phosphatidylinositol monophosphates. The KRKK motif within the VHS domain is required for binding to phosphatidylinositol monophosphates, with a preference for phosphatidylinositol 5-phosphate (PtdIns(5)P).

Similarity. Belongs to the TOM1 family.

Isoforms (4)

UniProt ID	Names	Canonical?
O60784-1	1	yes
O60784-2	2
O60784-3	3
O60784-4	4

RefSeq proteins (4): NP_001129201, NP_001129202, NP_001129204, NP_005479* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002014	VHS_dom	Domain
IPR004152	GAT_dom	Domain
IPR008942	ENTH_VHS	Homologous_superfamily
IPR014645	TOM1	Family
IPR038425	GAT_sf	Homologous_superfamily

Pfam: PF00790, PF03127

UniProt features (62 total): helix 14, mutagenesis site 12, modified residue 10, region of interest 5, compositionally biased region 3, splice variant 3, sequence variant 3, sequence conflict 3, turn 3, domain 2, chain 1, cross-link 1, strand 1, short sequence motif 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
9KZN	X-RAY DIFFRACTION	1.35
1ELK	X-RAY DIFFRACTION	1.5
1WRD	X-RAY DIFFRACTION	1.75
6J56	X-RAY DIFFRACTION	1.8
2N2N	SOLUTION NMR
2N9D	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60784-F1	71.67	0.46

Functional residue map

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

Post-translational modifications (11): 1, 11, 160, 164, 176, 180, 355, 376, 461, 462, 385

Mutagenesis-validated functional residues (12):

Position	Phenotype
48–57	reduced binding to phosphatidylinositol monophosphates.
223	reduced interaction with tollip.
227	reduced interaction with tollip.
230	reduced interaction with tollip. reduced localization to endosomal vesicles.
256	reduced interaction with ubc/ubiquitin.
257	reduced interaction with tollip.
264	reduced interaction with tollip.
267	reduced interaction with tollip.
285	reduced interaction with ubc/ubiquitin.
289	reduced interaction with ubc/ubiquitin.
321–325	fails to interact with clathrin heavy chain. diffuse localization throughout the cell.
362–364	reduced interaction with clathrin heavy chain.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 289 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_ENDOSOME_ORGANIZATION, GOBP_VACUOLE_ORGANIZATION, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, GOBP_VESICLE_ORGANIZATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, CMYB_01, GOBP_MEMBRANE_FUSION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_DISASSEMBLY, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_MACROAUTOPHAGY

GO Biological Process (8): endocytosis (GO:0006897), signal transduction (GO:0007165), protein transport (GO:0015031), endosomal transport (GO:0016197), substrate localization to autophagosome (GO:0061753), autophagosome-lysosome fusion (GO:0061909), positive regulation of autophagosome maturation (GO:1901098), regulation of endosome organization (GO:1904978)

GO Molecular Function (8): phosphatidylinositol-5-phosphate binding (GO:0010314), clathrin binding (GO:0030276), polyubiquitin modification-dependent protein binding (GO:0031593), clathrin heavy chain binding (GO:0032050), ubiquitin binding (GO:0043130), myosin VI binding (GO:0070853), protein binding (GO:0005515), phosphatidylinositol binding (GO:0035091)

GO Cellular Component (12): cytoplasm (GO:0005737), endosome (GO:0005768), early endosome (GO:0005769), Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), endosome membrane (GO:0010008), membrane (GO:0016020), early endosome membrane (GO:0031901), azurophil granule membrane (GO:0035577), specific granule membrane (GO:0035579), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
vesicle-mediated transport	2
anion binding	2
endomembrane system	2
endosome	2
cytoplasm	2
secretory granule membrane	2
vesicle budding from membrane	1
membrane invagination	1
import into cell	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
intracellular transport	1
autophagosome assembly	1
establishment of localization in cell	1
vesicle fusion	1
macroautophagy	1
positive regulation of organelle organization	1
positive regulation of macroautophagy	1
positive regulation of protein-containing complex disassembly	1
autophagosome maturation	1
regulation of autophagosome maturation	1
endosome organization	1
regulation of organelle organization	1
phosphatidylinositol phosphate binding	1
protein binding	1
modification-dependent protein binding	1
clathrin binding	1
ubiquitin-like protein binding	1
myosin binding	1
binding	1
intracellular anatomical structure	1
cytoplasmic vesicle	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1202 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TOM1	TOLLIP	Q9H0E2	989
TOM1	HMGXB4	Q9UGU5	924
TOM1	ZFYVE16	Q7Z3T8	884
TOM1	MCM5	P33992	844
TOM1	HUWE1	Q7Z6Z7	789
TOM1	ARL5B	Q96KC2	694
TOM1	LMTK2	Q8IWU2	666
TOM1	TSG101	Q99816	609
TOM1	EEA1	Q15075	586
TOM1	APPL1	Q9UKG1	574
TOM1	DAB2	P98082	571
TOM1	MYO6	Q9UM54	532
TOM1	CDKN2A	P42771	512
TOM1	TLR2	O60603	506
TOM1	HMOX2	P30519	491

IntAct

97 interactions, top by confidence:

A	B	Type	Score
TOM1	TOLLIP	psi-mi:“MI:0915”(physical association)	0.890
TOLLIP	TOM1	psi-mi:“MI:0915”(physical association)	0.890
TOLLIP	TOM1	psi-mi:“MI:0914”(association)	0.890
ARRDC3	WWP2	psi-mi:“MI:0914”(association)	0.770
TOM1	ZFYVE16	psi-mi:“MI:0915”(physical association)	0.740
UBB	TOM1	psi-mi:“MI:0407”(direct interaction)	0.740
TOM1	UBB	psi-mi:“MI:0407”(direct interaction)	0.740
MYO6	GIPC1	psi-mi:“MI:0914”(association)	0.690
TOM1	TOLLIP	psi-mi:“MI:0407”(direct interaction)	0.620
TOLLIP	TOM1	psi-mi:“MI:0915”(physical association)	0.560
TOM1	TOLLIP	psi-mi:“MI:0915”(physical association)	0.560
MYO6	TOM1	psi-mi:“MI:0914”(association)	0.530
CUEDC1	TOM1	psi-mi:“MI:0914”(association)	0.530
SLC15A4	PGRMC1	psi-mi:“MI:0914”(association)	0.530

BioGRID (176): TOLLIP (Two-hybrid), TOM1 (Affinity Capture-MS), TOM1 (Reconstituted Complex), TOLLIP (Reconstituted Complex), TOM1 (Biochemical Activity), TOM1 (Affinity Capture-MS), DOHH (Co-fractionation), TOM1 (Co-fractionation), TOM1 (Affinity Capture-MS), TOM1 (Affinity Capture-MS), TOM1 (Affinity Capture-MS), TOM1 (Affinity Capture-Western), TOM1 (Co-crystal Structure), TOLLIP (Reconstituted Complex), UBC (Co-crystal Structure)

ESM2 similar proteins: A0A0G2JV04, B0V207, D3Z8X7, D3ZFJ3, D3ZND0, F1LM81, G9CGD6, O00499, O08539, O08839, O12940, O60308, O60784, O75674, O88746, P42567, P55194, Q05DH4, Q0GNC1, Q0IHV1, Q27J81, Q3B7M3, Q3UN70, Q4KLN4, Q505K2, Q5FVK6, Q5T0F9, Q5U3K5, Q66HA5, Q68EF0, Q6P1N0, Q6P5E6, Q6P9Q4, Q6P9Q6, Q80V31, Q80V94, Q8BMI3, Q8BRN9, Q8K1A6, Q8R0H9

Diamond homologs: A0A0G2JV04, A3LXQ8, F4KAU9, O01498, O14964, O43747, O60784, O75843, O75886, O88512, O88746, O93436, P22892, P70297, Q0V8S0, Q5R5M2, Q68FJ8, Q6P5E6, Q8BMI3, Q8R0H9, Q92783, Q960X8, Q99LI8, Q9JJ50, Q9NZ52, Q9UJY4, Q9UJY5, A0A0D1E015, A0JMD2, A1CEK1, A1DFN5, A1DFP5, A2QWA2, A3LX75, A4QTV1, A8QCE4, A8XJZ8, B0WAQ0, B3MT31, B3P851

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SMURF1	unknown	TOM1	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	66
Likely benign	4
Benign	8

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1224492	NM_005488.3(TOM1):c.920G>A (p.Gly307Asp)	Pathogenic

SpliceAI

2531 predictions. Top by Δscore:

Variant	Effect	Δscore
22:35299979:CGGT:C	donor_loss	1.0000
22:35299981:G:A	donor_loss	1.0000
22:35299981:G:GG	donor_gain	1.0000
22:35299982:T:A	donor_loss	1.0000
22:35317957:G:GT	donor_gain	1.0000
22:35317960:GG:G	donor_gain	1.0000
22:35317961:GG:G	donor_gain	1.0000
22:35321957:A:AG	acceptor_gain	1.0000
22:35321958:G:GA	acceptor_gain	1.0000
22:35321958:GT:G	acceptor_gain	1.0000
22:35321958:GTC:G	acceptor_gain	1.0000
22:35321958:GTCC:G	acceptor_gain	1.0000
22:35321958:GTCCC:G	acceptor_gain	1.0000
22:35322038:G:GG	donor_gain	1.0000
22:35323175:CAGG:C	donor_loss	1.0000
22:35323176:AGGTG:A	donor_loss	1.0000
22:35323177:GGT:G	donor_loss	1.0000
22:35323178:G:GG	donor_gain	1.0000
22:35323178:GTGA:G	donor_loss	1.0000
22:35323179:T:G	donor_loss	1.0000
22:35323492:TCAG:T	acceptor_loss	1.0000
22:35323494:A:AG	acceptor_gain	1.0000
22:35323494:AG:A	acceptor_loss	1.0000
22:35323495:G:GA	acceptor_gain	1.0000
22:35323495:GT:G	acceptor_gain	1.0000
22:35323495:GTC:G	acceptor_gain	1.0000
22:35323495:GTCCT:G	acceptor_gain	1.0000
22:35323627:GAGG:G	donor_gain	1.0000
22:35323629:GG:G	donor_gain	1.0000
22:35323630:GG:G	donor_gain	1.0000

AlphaMissense

3217 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:35323499:T:A	W124R	1.000
22:35323499:T:C	W124R	1.000
22:35323560:T:C	L144P	1.000
22:35299968:G:A	G14R	0.999
22:35299968:G:C	G14R	0.999
22:35317882:G:C	A20P	0.999
22:35317935:C:G	C37W	0.999
22:35322033:T:C	L71P	0.999
22:35323040:T:C	C77R	0.999
22:35323054:C:G	C81W	0.999
22:35323164:T:C	L118P	0.999
22:35323170:T:C	L120P	0.999
22:35323580:T:C	F151L	0.999
22:35323581:T:C	F151S	0.999
22:35323582:C:A	F151L	0.999
22:35323582:C:G	F151L	0.999
22:35330351:T:C	L257P	0.999
22:35330432:T:C	L284P	0.999
22:35330435:T:C	L285P	0.999
22:35330453:T:C	L291P	0.999
22:35299969:G:A	G14E	0.998
22:35317883:C:A	A20D	0.998
22:35317886:C:A	T21K	0.998
22:35317912:T:A	W30R	0.998
22:35317912:T:C	W30R	0.998
22:35317933:T:C	C37R	0.998
22:35317934:G:A	C37Y	0.998
22:35321969:G:C	A50P	0.998
22:35322033:T:A	L71H	0.998
22:35322033:T:G	L71R	0.998

dbSNP variants (sampled 300 via entrez): RS1000091351 (22:35322691 C>G,T), RS1000095565 (22:35323255 G>A), RS1000142057 (22:35328522 A>G), RS1000147599 (22:35323408 A>G), RS1000197920 (22:35346803 G>A,T), RS1000257669 (22:35308203 C>A,T), RS1000286243 (22:35301753 C>T), RS1000297058 (22:35325320 G>A), RS1000348096 (22:35328830 C>T), RS1000360442 (22:35302135 T>C), RS1000367131 (22:35298524 C>A), RS1000403295 (22:35340722 G>A,C), RS1000406025 (22:35334835 C>A,G,T), RS1000406027 (22:35330691 G>A), RS1000419424 (22:35298846 T>C)

Disease associations

OMIM: gene MIM:604700 | disease phenotypes: MIM:619510

GenCC curated gene-disease

Disease	Classification	Inheritance
immune system disorder	Limited	Autosomal dominant
immunodeficiency 85 and autoimmunity	Limited	Unknown

Mondo (2): immunodeficiency 85 and autoimmunity (MONDO:0030428), immune system disorder (MONDO:0005046)

Orphanet (0):

HPO phenotypes

24 total (24 of 24 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000964	Eczematoid dermatitis
HP:0001019	Erythroderma
HP:0001510	Growth delay
HP:0001531	Failure to thrive in infancy
HP:0001888	Decreased total lymphocyte count
HP:0002013	Vomiting
HP:0002028	Chronic diarrhea
HP:0002205	Recurrent respiratory infections
HP:0002206	Pulmonary fibrosis
HP:0002720	Decreased circulating IgA concentration
HP:0002850	Decreased circulating total IgM
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0004315	Decreased circulating IgG concentration
HP:0005403	Decreased total T cell count
HP:0005479	Decreased circulating IgE concentration
HP:0011473	Villous atrophy
HP:0020072	Persistent EBV viremia
HP:0030374	Decreased proportion of memory B cells
HP:0032218	Decreased CD4+ T cell proportion
HP:0033454	Tube feeding
HP:0040218	Reduced total natural killer cell count
HP:0040313	Oligoarthritis

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST002221_41	Cholesterol, total	5.000000e-08
GCST002921_2	Multiple myeloma	6.000000e-08
GCST002922_2	Multiple myeloma and monoclonal gammopathy	3.000000e-07
GCST004131_135	Inflammatory bowel disease	8.000000e-06
GCST004133_78	Ulcerative colitis	3.000000e-08
GCST004235_46	Total cholesterol levels	2.000000e-08
GCST005958_13	Waist-to-hip ratio adjusted for BMI (age >50)	1.000000e-06
GCST005962_33	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	6.000000e-06
GCST006284_15	Plasma proprotein convertase subtilisin/kexin type 9 levels in stable coronary artery disease	2.000000e-06
GCST006284_7	Plasma proprotein convertase subtilisin/kexin type 9 levels in stable coronary artery disease	6.000000e-07
GCST006306_3	HDL cholesterol	2.000000e-06
GCST007013_1	Hippocampal volume in mild cognitive impairment	2.000000e-07
GCST008035_110	High density lipoprotein cholesterol levels	4.000000e-08
GCST008035_68	High density lipoprotein cholesterol levels	9.000000e-06
GCST010204_164	Low density lipoprotein cholesterol levels	6.000000e-09
GCST012048_21	Triglyceride levels	4.000000e-07
GCST90020026_216	Hip index	2.000000e-08
GCST90020028_1548	Hip circumference adjusted for BMI	1.000000e-10

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004574	total cholesterol measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0006899	PCSK9 protein measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0005035	hippocampal volume
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007154	Immune System Diseases	C20

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

37 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects expression	3
Cadmium Chloride	increases expression	2
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects localization, decreases expression, affects cotreatment	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
nickel sulfate	increases expression	1
coumarin	decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
Arsenic Trioxide	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	affects phosphorylation	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Furaldehyde	affects cotreatment, affects localization, decreases expression, increases expression	1
Hydrogen Peroxide	increases expression	1
Ivermectin	decreases expression	1
Methotrexate	decreases expression	1
Potassium Dichromate	increases expression	1
Smoke	increases expression	1
Sodium Chloride	decreases expression, increases expression, affects cotreatment, affects localization	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TT22	HAP1 TOM1 (-) 1	Cancer cell line	Male
CVCL_TT23	HAP1 TOM1 (-) 2	Cancer cell line	Male
CVCL_TT24	HAP1 TOM1 (-) 3	Cancer cell line	Male
CVCL_TT25	HAP1 TOM1 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02053740	PHASE4	COMPLETED	Use of Traditional Chinese Medicine (Ren Shen Yang Rong Tang) Against Microinflammation in Hemodialysis Patients: A Quasi-randomized Controlled Trial
NCT01002742	PHASE3	COMPLETED	Acute Graft-versus-Host Disease Treatment (BMT CTN 0802)
NCT00224874	PHASE2	COMPLETED	Treatment for Acute Graft-Versus-Host Disease (BMT CTN 0302)
NCT02519816	PHASE2	UNKNOWN	Continuous Alloreactive T Cell Depletion and Regulatory T Cell Expansion for the Treatment of Steroid-refractory or Dependent Chronic GVHD
NCT03744676	PHASE2	COMPLETED	A Safety Trial of Lisocabtagene Maraleucel (JCAR017) for Relapsed and Refractory (R/R) B-cell Non-Hodgkin Lymphoma (NHL) in the Outpatient Setting (TRANSCEND-OUTREACH-007)
NCT05507242	PHASE2	RECRUITING	Effects of Blocking TSLP on Airway Inflammation and the Epithelial Immune-response to Exacerbation Triggers in Patients With COPD
NCT00008450	PHASE1	COMPLETED	Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant
NCT03351543	PHASE1	COMPLETED	Effect of Microbial Exposure on Health, Particularly Immune System
NCT03357939	PHASE1	COMPLETED	Phase I Study of HLX3 vs Adalimumab in Chinese Healthy Subjects
NCT05806567	PHASE1	COMPLETED	A Study to Assess the Effect of Oral Belumosudil on Inhibition of Various Proteins in the Fed State in Healthy Male Subjects
NCT05918588	PHASE1	COMPLETED	A Study to Determine the Effect of Multiple Oral Doses and Regimens of KD025 in Healthy Male and Post-menopausal Female Subjects
NCT05918614	PHASE1	COMPLETED	A Study to Determine the Effect of 500 mg Oral Dose of KD025 in Healthy Male and Post-menopausal Female Subjects
NCT05918627	PHASE1	COMPLETED	A Study to Determine the Effect of Multiple Oral Doses of SLx-2119 in Healthy Male Subjects
NCT04294459	PHASE1/PHASE2	TERMINATED	Safety, Pharmacokinetics, and Preliminary Efficacy of Isatuximab in Patients Awaiting Kidney Transplantation
NCT04928963	PHASE1/PHASE2	UNKNOWN	Fighting Immunosenescence and Promoting Immunity by a Fasting-mimicking Diet Elderly.
NCT01367821	Not specified	UNKNOWN	Immune Function in Patients With Obstructive Jaundice
NCT01821820	Not specified	COMPLETED	Pistachios, Performance, Metabolomics
NCT02417766	Not specified	COMPLETED	NIAID Clinical Center Genomics Opportunity Protocol
NCT02824237	Not specified	UNKNOWN	GEOHealth Hub: Household Air Pollution and Cardio-pulmonary and Immune Function Outcomes
NCT02981992	Not specified	COMPLETED	T Regulatory Cells in Hemodialysis Patients: Observational Study
NCT03207854	Not specified	RECRUITING	Collection of Immunology Specimens From Patients With Cancer or Blood Disorders, and Healthy Volunteers
NCT03364699	Not specified	COMPLETED	Fish Oils and Soybean Lecithin Supplementation Modulate Immune Function in Runners
NCT03370627	Not specified	COMPLETED	Effect of Anti-CD303 Antibodies in Autoimmune Diseases
NCT03385850	Not specified	COMPLETED	The Th17/Treg Cells and IL-23/IL-17 Axis and Early Enteral Nutrition in Sepsis
NCT03908736	Not specified	RECRUITING	Thinking Zinc: a Study of Zinc Supplements on the Navajo Nation
NCT03994302	Not specified	COMPLETED	Monitoring the Antiphospholipid Syndrome:TOXicity of Drugs (APSTOX)
NCT04386395	Not specified	COMPLETED	Immune Changes in Severe COVID-19 Pulmonary Infections
NCT04430972	Not specified	NOT_YET_RECRUITING	Immune Responsiveness and Outcome After Aortic Valve Surgery (Measure)
NCT04444609	Not specified	UNKNOWN	PROSAIC-19 - Prospective Longitudinal Assessment in a COVID-19 Infected Cohort
NCT04445402	Not specified	COMPLETED	Pediatrics HOT COVID-19 Database in NY Tristate
NCT04458246	Not specified	UNKNOWN	Home-based Aerobic Training Among Adolescents With Chronic Diseases During COVID-19 Pandemic
NCT04802044	Not specified	UNKNOWN	COVID-19, Aging, and Cardiometabolic Risk Factors Study
NCT04830046	Not specified	COMPLETED	Covid-19 Vaccine Responsiveness in MM and Waldenstrom
NCT05000307	Not specified	COMPLETED	Co-Sér: Serological Analysis and Viral Neutralization in People With a Documented COVID-19 Infection
NCT05002023	Not specified	RECRUITING	PRINCE Study - Cohort Study of Healthy Pregnant Women Followed by the Assessment of Children´s Health and Immunity
NCT05139706	Not specified	RECRUITING	Montreal Immune-Related Adverse Events (MIRAE) Study
NCT05219890	Not specified	WITHDRAWN	Transcriptomics of Mononuclear Cells and Inflammatory Status of Obese Patients Treated With Omega-3 Fatty Acids
NCT05266664	Not specified	RECRUITING	Preterm Immune System Development and Response to Immunization
NCT05318196	Not specified	RECRUITING	Molecular Prediction of Development, Progression or Complications of Kidney, Immune or Transplantation-related Diseases
NCT05367986	Not specified	COMPLETED	Electro-acupuncture at Zusanli, Qihai, and Guanyuan Acupoints Regulate Immune Function in Patients With Sepsis