LHFPL3

Summary

LHFPL3 (LHFPL tetraspan subfamily member 3, HGNC:6589) is a protein-coding gene on chromosome 7q22.2-q22.3, encoding LHFPL tetraspan subfamily member 3 protein (Q86UP9).

This gene is a member of the lipoma HMGIC fusion partner (LHFP) gene family, which is a subset of the superfamily of tetraspan transmembrane protein encoding genes. Mutations in one LHFP-like gene result in deafness in humans and mice, and a second LHFP-like gene is fused to a high-mobility group gene in a translocation-associated lipoma. A partial gene fragment named LHFPL4 corresponds to a portion of the first exon of this gene.

Source: NCBI Gene 375612 — RefSeq curated summary.

At a glance

• GWAS associations: 17
• Clinical variants (ClinVar): 59 total — 1 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_199000

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6589
Approved symbol	LHFPL3
Name	LHFPL tetraspan subfamily member 3
Location	7q22.2-q22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000187416
Ensembl biotype	protein_coding
OMIM	609719
Entrez	375612

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000401970, ENST00000424859, ENST00000683240, ENST00000684090

RefSeq mRNA: 2 — MANE Select: NM_199000 NM_001386065, NM_199000

CCDS: CCDS94167, CCDS94168

Canonical transcript exons

ENST00000424859 — 3 exons

Exon	Start	End
ENSE00001349915	104736675	104736911
ENSE00001554382	104328603	104329224
ENSE00001723245	104906187	104908561

Expression profiles

Bgee: expression breadth ubiquitous, 123 present calls, max score 97.87.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4230 / max 30.9116, expressed in 104 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
80291	0.3276	99
80292	0.0954	59

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	97.87	gold quality
dorsal plus ventral thalamus	UBERON:0001897	92.01	gold quality
subthalamic nucleus	UBERON:0001906	88.32	gold quality
inferior vagus X ganglion	UBERON:0005363	88.07	gold quality
ventral tegmental area	UBERON:0002691	87.82	gold quality
lateral globus pallidus	UBERON:0002476	86.12	gold quality
amygdala	UBERON:0001876	85.54	gold quality
corpus callosum	UBERON:0002336	83.35	gold quality
Brodmann (1909) area 46	UBERON:0006483	83.10	gold quality
hypothalamus	UBERON:0001898	82.37	gold quality
superior vestibular nucleus	UBERON:0007227	82.26	gold quality
temporal lobe	UBERON:0001871	82.23	gold quality
medulla oblongata	UBERON:0001896	82.16	gold quality
midbrain	UBERON:0001891	82.14	gold quality
substantia nigra	UBERON:0002038	81.97	gold quality
nucleus accumbens	UBERON:0001882	81.83	gold quality
anterior cingulate cortex	UBERON:0009835	81.29	gold quality
caudate nucleus	UBERON:0001873	81.15	gold quality
pancreatic ductal cell	CL:0002079	80.36	silver quality
Ammon’s horn	UBERON:0001954	79.71	gold quality
putamen	UBERON:0001874	79.50	gold quality
substantia nigra pars compacta	UBERON:0001965	79.38	gold quality
substantia nigra pars reticulata	UBERON:0001966	79.34	gold quality
prefrontal cortex	UBERON:0000451	79.18	gold quality
entorhinal cortex	UBERON:0002728	78.00	gold quality
ventricular zone	UBERON:0003053	77.58	gold quality
dorsal root ganglion	UBERON:0000044	77.54	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.44	silver quality
cerebral cortex	UBERON:0000956	77.41	gold quality
ganglionic eminence	UBERON:0004023	77.34	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	5880.07
E-HCAD-30	yes	5622.44
E-HCAD-25	yes	4623.17
E-GEOD-180759	yes	4551.98
E-GEOD-84465	yes	26.58
E-GEOD-93593	yes	4.94
E-ANND-3	yes	3.29

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

137 targeting LHFPL3, 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-7110-3P	100.00	73.18	2486
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-12136	99.98	72.81	5713
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-335-3P	99.93	73.36	4958

Literature-anchored findings (GeneRIF, showing 2)

• The authors present an overview of the LHFP gene family in mouse and humans (PMID:15905332)
• Results show that miR-218-5p targeting lipoma HMGIC fusion partner-like 3 protein (LHFPL3) mRNA plays significant roles in preventing the invasiveness of glioma cells. (PMID:30314994)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	lhfpl3	ENSDARG00000021595
mus_musculus	Lhfpl3	ENSMUSG00000106379
rattus_norvegicus	LOC103692025	ENSRNOG00000066703
drosophila_melanogaster	Tmhs	FBGN0262624

Paralogs (6): LHFPL2 (ENSG00000145685), LHFPL4 (ENSG00000156959), LHFPL1 (ENSG00000182508), LHFPL6 (ENSG00000183722), LHFPL5 (ENSG00000197753), LHFPL7 (ENSG00000206069)

Protein

Protein identifiers

LHFPL tetraspan subfamily member 3 protein — Q86UP9 (reviewed: Q86UP9)

Alternative names: Lipoma HMGIC fusion partner-like 3 protein

All UniProt accessions (3): Q86UP9, A0A804HL93, A1L384

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Membrane.

Similarity. Belongs to the LHFP family.

RefSeq proteins (2): NP_001372994, NP_945351* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019372	LHFPL	Family

Pfam: PF10242

UniProt features (6 total): transmembrane region 4, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86UP9-F1	88.73	0.58

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 192 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, BENPORATH_ES_WITH_H3K27ME3, GOBP_SYNAPSE_ASSEMBLY, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, CACCAGC_MIR138, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_REGULATION_OF_SYNAPSE_ASSEMBLY, GOBP_POSTSYNAPTIC_MEMBRANE_ORGANIZATION, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, GOBP_REGULATION_OF_SYNAPSE_STRUCTURE_OR_ACTIVITY, AACTTT_UNKNOWN

GO Biological Process (1): sensory perception of sound (GO:0007605)

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

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sensory perception of mechanical stimulus	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1076 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LHFPL3	NLGN2	Q8NFZ4	901
LHFPL3	GPHN	Q9NQX3	682
LHFPL3	COL11A2	P13942	605
LHFPL3	HSPB3	Q12988	490
LHFPL3	THUMPD3	Q9BV44	487
LHFPL3	INSYN1	Q2T9L4	450
LHFPL3	SLC44A5	Q8NCS7	437
LHFPL3	NOL4	O94818	432
LHFPL3	DEFB107A	Q8IZN7	406
LHFPL3	IGSF9B	Q9UPX0	399
LHFPL3	SGCD	Q92629	398
LHFPL3	SSBP1	Q04837	396
LHFPL3	ARHGEF9	O43307	392
LHFPL3	TBCEL	Q5QJ74	391
LHFPL3	ABCC2	Q92887	387

IntAct

10 interactions, top by confidence:

A	B	Type	Score
LHFPL3	PIGP	psi-mi:“MI:0915”(physical association)	0.560
TNFSF14	LHFPL3	psi-mi:“MI:0915”(physical association)	0.560
PIGP	LHFPL3	psi-mi:“MI:0915”(physical association)	0.560
LHFPL3	RNF24	psi-mi:“MI:0915”(physical association)	0.560
LHFPL3	TNFSF14	psi-mi:“MI:0915”(physical association)	0.000
LHFPL3	RNF24	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (3): LHFPL3 (Two-hybrid), LHFPL3 (Two-hybrid), LHFPL3 (Two-hybrid)

ESM2 similar proteins: A2VE61, A6QNL6, Q0IHU6, Q0VFK3, Q17QL9, Q17R16, Q2YDG0, Q32NX4, Q3KRC4, Q3URJ8, Q401C0, Q4KMZ8, Q4PNJ2, Q5BL21, Q5R7B1, Q5R9I4, Q5RET6, Q5U4E0, Q5VXU1, Q5ZMP3, Q61088, Q66IV3, Q66KY5, Q68EY2, Q6DD32, Q6DEX3, Q6DHB5, Q6NYY9, Q6P360, Q6PHL4, Q7TSY2, Q7Z7J7, Q810F1, Q86UP9, Q8BXA5, Q8IVV8, Q8IWA5, Q8K3J9, Q8N8D7, Q8WVP7

Diamond homologs: Q17R16, Q4KL25, Q5PPI7, Q5U4E0, Q66IV3, Q6DHB5, Q7TSY2, Q7Z7J7, Q7ZZL8, Q86UP9, Q8TAF8, Q9CTN8, Q5BJS2, Q8BM86, Q9Y693

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	43
Likely benign	6
Benign	2

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3391878	GRCh37/hg19 3p25.3(chr3:9506164-9561205)x1	Pathogenic
442033	GRCh37/hg19 3p25.3(chr3:9421663-9574327)x1	Likely pathogenic

SpliceAI

3625 predictions. Top by Δscore:

Variant	Effect	Δscore
7:104329221:TCCGG:T	donor_loss	1.0000
7:104329222:CCGG:C	donor_loss	1.0000
7:104329223:CGGTG:C	donor_loss	1.0000
7:104329224:GGT:G	donor_loss	1.0000
7:104329225:G:GA	donor_loss	1.0000
7:104329226:T:A	donor_loss	1.0000
7:104693315:T:G	donor_gain	1.0000
7:104736672:A:AG	acceptor_gain	1.0000
7:104736672:AAGCT:A	acceptor_gain	1.0000
7:104736673:A:G	acceptor_gain	1.0000
7:104736674:G:GG	acceptor_gain	1.0000
7:104736674:GCT:G	acceptor_gain	1.0000
7:104736910:AGG:A	donor_loss	1.0000
7:104736912:G:GA	donor_loss	1.0000
7:104736913:T:A	donor_loss	1.0000
7:104329197:A:G	donor_gain	0.9900
7:104329225:G:GG	donor_gain	0.9900
7:104329227:GAGT:G	donor_loss	0.9900
7:104398079:A:G	acceptor_gain	0.9900
7:104398186:G:GG	donor_gain	0.9900
7:104554409:G:GT	donor_gain	0.9900
7:104604933:TCACA:T	donor_gain	0.9900
7:104629332:A:T	donor_gain	0.9900
7:104647813:A:T	donor_gain	0.9900
7:104693308:GAA:G	donor_gain	0.9900
7:104736651:T:TA	acceptor_gain	0.9900
7:104736669:TCCAA:T	acceptor_loss	0.9900
7:104736670:CCAA:C	acceptor_loss	0.9900
7:104736671:CAA:C	acceptor_loss	0.9900
7:104736672:AAG:A	acceptor_loss	0.9900

AlphaMissense

1454 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000000207 (7:104749954 G>A,T), RS1000003388 (7:104450422 A>G), RS1000005886 (7:104412823 A>C,G), RS1000016791 (7:104487686 C>G,T), RS1000017033 (7:104792084 A>T), RS1000024999 (7:104362598 C>T), RS1000025472 (7:104493949 T>C), RS1000028297 (7:104331296 A>G), RS1000031085 (7:104789003 G>A,C,T), RS1000031753 (7:104470672 C>T), RS1000032516 (7:104806730 C>A,G,T), RS1000034481 (7:104657532 A>G), RS1000034874 (7:104619125 T>C), RS1000037390 (7:104474616 G>T), RS1000037915 (7:104582043 GA>G)

Disease associations

OMIM: gene MIM:609719 | disease phenotypes: MIM:114480, MIM:615761

GenCC curated gene-disease

Mondo (2): hereditary breast carcinoma (MONDO:0016419), intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (MONDO:0014336)

Orphanet (2): Hereditary breast cancer (Orphanet:227535), OBSOLETE: Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (Orphanet:404440)

HPO phenotypes

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

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST001057_2	Obesity	7.000000e-07
GCST001356_31	Gout	1.000000e-07
GCST002045_8	Educational attainment	6.000000e-06
GCST002367_14	Social communication problems	6.000000e-06
GCST003194_26	Fibrinogen levels	2.000000e-08
GCST003518_2	Daytime sleep phenotypes	1.000000e-06
GCST004521_190	Autism spectrum disorder or schizophrenia	3.000000e-10
GCST005023_42	Initial pursuit acceleration	1.000000e-06
GCST006479_96	Diverticular disease	2.000000e-06
GCST006922_16	Regular attendance at a religious group	8.000000e-10
GCST007100_7	Asthma exacerbations in inhaled corticosteroid treatment	3.000000e-06
GCST007673_11	3-month functional outcome in ischaemic stroke (modified Rankin score)	3.000000e-06
GCST008152_121	Weight	4.000000e-06
GCST011741_54	LDL cholesterol levels in HIV infection	7.000000e-06
GCST012145_23	Ferritin levels	4.000000e-07
GCST012486_3	Response to lithium treatment in bipolar disorder (dichotomous phenotype)	4.000000e-07
GCST012489_141	Heel bone mineral density x serum urate levels interaction	2.000000e-08

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004784	self reported educational attainment
EFO:0005427	social communication impairment
EFO:0007828	daytime rest measurement
EFO:0008434	initial pursuit acceleration
EFO:0009959	diverticular disease
EFO:0009592	social interaction measurement
EFO:0007614	asthma exacerbation measurement
EFO:0009603	stroke outcome severity measurement
EFO:0004338	body weight
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004459	ferritin measurement
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C562840	Breast Cancer, Familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs61585310	LHFPL3		0.00	0

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
propionaldehyde	increases methylation	1
bisphenol A	affects cotreatment, increases expression	1
nonanal	increases methylation	1
n-hexanal	increases methylation	1
arsenite	decreases methylation	1
butyraldehyde	increases methylation	1
benzo(e)pyrene	increases methylation	1
caprylic aldehyde	increases methylation	1
pentanal	increases methylation	1
heptanal	increases methylation	1
CGP 52608	affects binding, increases reaction	1
Resveratrol	affects cotreatment, increases expression	1
Benzo(a)pyrene	increases methylation	1
Copper	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Indomethacin	increases expression, affects cotreatment	1
Methapyrilene	increases methylation	1
Valproic Acid	increases methylation	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00040222	Not specified	COMPLETED	Clinical, Genetic, Behavioral, Laboratory and Epidemiologic Characterization of Individuals and Families at High Risk of Breast/Ovarian Cancer
NCT02557776	Not specified	COMPLETED	Written Genetic Counseling and Mutation Analysis of BRCA1 and BRCA2 to Patients With Breast Cancer
NCT03495544	Not specified	UNKNOWN	Study Estimating Association Between Germline Mutations and PD-L1 Expression in Breast Cancer
NCT03959267	Not specified	COMPLETED	Testing a Culturally Adapted Telephone Genetic Counseling Intervention
NCT04058418	Not specified	COMPLETED	Specialist Recommendation on FBC (Familial Breast Cancer) Chemoprevention Prescribing
NCT04125914	Not specified	ACTIVE_NOT_RECRUITING	Weight Management and Health Behavior Intervention in Lowering Cancer Risk for BRCA Positive and Lynch Syndrome Families
NCT04169542	Not specified	RECRUITING	Impact of COVID-19 Pandemic on Out-of-Pocket Costs, Lost Wages, and Unemployment in Patients With Breast Cancer Undergoing Breast Surgery
NCT04197856	Not specified	ACTIVE_NOT_RECRUITING	Direct Information to At-risk Relatives
NCT07292246	Not specified	RECRUITING	A Prospective CohorT Study of HandX - Assisted ENdoscopic MAstectomy: Feasibility and Safety (ATHENA I Study)
NCT07307664	Not specified	RECRUITING	Increasing Germline Genetic Testing for Patients With Cancer