LEMD3

Summary

LEMD3 (LEM domain containing 3, HGNC:28887) is a protein-coding gene on chromosome 12q14.3, encoding Inner nuclear membrane protein Man1 (Q9Y2U8). Can function as a specific repressor of TGF-beta, activin, and BMP signaling through its interaction with the R-SMAD proteins. It is haploinsufficient (ClinGen: sufficient evidence).

This locus encodes a LEM domain-containing protein. The encoded protein functions to antagonize transforming growth factor-beta signaling at the inner nuclear membrane. Two transcript variants encoding different isoforms have been found for this gene. Mutations in this gene have been associated with osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis.

Source: NCBI Gene 23592 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Buschke-Ollendorff syndrome (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 14
• Clinical variants (ClinVar): 936 total — 52 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 85
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_014319

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28887
Approved symbol	LEMD3
Name	LEM domain containing 3
Location	12q14.3
Locus type	gene with protein product
Status	Approved
Aliases	MAN1
Ensembl gene	ENSG00000174106
Ensembl biotype	protein_coding
OMIM	607844
Entrez	23592

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000308330, ENST00000539442, ENST00000541171, ENST00000542032, ENST00000544506, ENST00000545026, ENST00000883212, ENST00000883213, ENST00000935241, ENST00000970054, ENST00000970055

RefSeq mRNA: 2 — MANE Select: NM_014319 NM_001167614, NM_014319

CCDS: CCDS8972

Canonical transcript exons

ENST00000308330 — 13 exons

Exon	Start	End
ENSE00000751368	65210926	65210963
ENSE00000751406	65215977	65216043
ENSE00000751407	65218552	65218619
ENSE00000751408	65238502	65238581
ENSE00000751409	65238669	65238814
ENSE00000751410	65239929	65240030
ENSE00000751411	65240136	65240238
ENSE00000751412	65240909	65241087
ENSE00000751414	65245669	65245774
ENSE00001208170	65169583	65171118
ENSE00001248858	65246162	65248355
ENSE00003582779	65245861	65245939
ENSE00003593316	65243388	65243469

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 96.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.7532 / max 175.1359, expressed in 1800 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
126484	18.3294	1796
126485	1.4239	504

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	96.35	gold quality
cerebellar vermis	UBERON:0004720	95.53	gold quality
germinal epithelium of ovary	UBERON:0001304	95.20	gold quality
visceral pleura	UBERON:0002401	94.58	gold quality
superficial temporal artery	UBERON:0001614	94.55	gold quality
trabecular bone tissue	UBERON:0002483	94.54	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.24	gold quality
tibia	UBERON:0000979	94.07	gold quality
choroid plexus epithelium	UBERON:0003911	93.77	gold quality
parietal pleura	UBERON:0002400	93.76	gold quality
epithelium of nasopharynx	UBERON:0001951	93.63	gold quality
nasopharynx	UBERON:0001728	93.61	gold quality
middle temporal gyrus	UBERON:0002771	93.60	gold quality
bronchial epithelial cell	CL:0002328	93.42	gold quality
adult organism	UBERON:0007023	93.36	gold quality
pleura	UBERON:0000977	93.22	gold quality
esophagus squamous epithelium	UBERON:0006920	93.22	gold quality
pigmented layer of retina	UBERON:0001782	93.14	gold quality
corpus epididymis	UBERON:0004359	92.98	gold quality
caput epididymis	UBERON:0004358	92.90	gold quality
mucosa of paranasal sinus	UBERON:0005030	92.89	gold quality
gingival epithelium	UBERON:0001949	92.65	gold quality
bone marrow	UBERON:0002371	92.45	gold quality
cauda epididymis	UBERON:0004360	92.39	gold quality
pons	UBERON:0000988	92.35	gold quality
cardia of stomach	UBERON:0001162	92.31	gold quality
jejunal mucosa	UBERON:0000399	92.28	gold quality
penis	UBERON:0000989	92.21	gold quality
urethra	UBERON:0000057	92.19	gold quality
mucosa of sigmoid colon	UBERON:0004993	92.09	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.23

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXH1, OVOL1

miRNA regulators (miRDB)

170 targeting LEMD3, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-656-3P	100.00	72.15	2788
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-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4789-5P	99.98	70.76	2721
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-19B-3P	99.98	75.44	2754
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-548AJ-3P	99.96	73.38	5345

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 25)

• Binds to Smad2 and Smad3 and antagonizes signaling by transforming growth factor-beta (PMID:15601644)
• The C-terminal domain of human MAN1 binds to Smad2 and Smad3 and antagonizes signaling by transforming growth factor-beta (PMID:15601644)
• Overexpression results in inhibition of R-Smad phosphorylation, heterodimerization with Smad4, and nuclear translocation (PMID:15647271)
• Data describe the direct binding of the nuclear membrane protein MAN1 to emerin in vitro. (PMID:15681850)
• germline LEMD3 mutations are rare in sporadic patients with isolated melorheostosis (PMID:16470551)
• MAN1 binds simultaneously to R-Smads and their targeted DNA sequences (PMID:16648637)
• novel mutation associated with familial cutaneous collagenomas (PMID:17223882)
• novel heterozygous splice-site mutation in a Japanese kindred with Buschke-Ollendorff syndrome (PMID:17505164)
• The LEMD3 mutation reported was clearly the cause of osteopoikilosis in the two families but its relationship to melorheostosis in one of the family members is still unclear. (PMID:17622481)
• Identified two mutations in the two cases of Buschke-Ollendorff syndrome. The mutation (c.2564G>A) is novel. The present study supports the general conclusion that LEMD3 mutations do not contribute to isolated sporadic melorheostosis. (PMID:19438932)
• Absence of LEMD3 mutation in the exons and splice sites of a family with BOS suggests that there is genetic heterogeneity for this disorder. (PMID:20083694)
• We found a novel c.2203C > T (p.R735X) mutation in exon 9 of LEMD3, resulting in a premature stop codon at amino acid position 735. (PMID:20618940)
• Genetic analyses of three generations of a family with Buschke-Ollendorff syndrome having a variable phenotype showed a novel c.2203C>T nonsense mutation at the LEMD3 locus. The mutation induced a change in the 735 arginine codon to a stop codon. (PMID:20678097)
• Buschke-Ollendorff syndrome in a three-generation family: influence of a novel LEMD3 mutation to tropoelastin expression. (PMID:20732851)
• The absence of direct binding of BAF to MAN1-C eliminates disruption of this interaction as the cause of the premature aging phenotype. (PMID:21966431)
• a nuclear envelope-localized mechanism of inactivating TGF-beta signaling in which MAN1 competes with transcription factors for binding to Smad2 and Smad3 and facilitates their dephosphorylation by PPM1A. (PMID:23779087)
• Data indicate that the inner nuclear membrane protein MAN1 directly binds the transcription activator BMAL1 promoter and enhances its transcription. (PMID:25182847)
• A novel mutation in LEMD3 splice site results in Buschke-Ollendorff syndrome. (PMID:26135202)
• LAMD3 Y871X mutation is associated with osteopoikilosis. (PMID:26694706)
• Letter/Case-Report: novel frameshift mutation in RNA recognition motif of LEMD3 in patient with Buschke-Ollendorff syndrome. (PMID:26711937)
• studies demonstrated that lower levels of MAN1 in differentiating MSC are associated with higher osteogenesis and lower adipogenesis. High levels of MAN1 only affected adipogenesis. (PMID:28449239)
• Here we describe the unusual case of a 60-year-old woman with isolated nevus elasticus and a mutation in the LEMD3 (LEM Domain Containing 3) gene. (PMID:29465813)
• LEMD3 is cleaved by PPM1a into fragments that enter the cytosol to bind SMAD2 and SMAD3, thereby antagonizing signaling initiated by stiffness-triggered activity of TGFbeta. (PMID:30108174)
• analysis of the structural basis for R-SMAD recognition by MAN1 using SMAD2-MAN1 and SMAD1-MAN1 complex structures (PMID:30321401)
• Melorheostosis and Osteopoikilosis Clinical and Molecular Description of an Italian Case Series. (PMID:31129707)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	lemd3	ENSDARG00000015824
mus_musculus	Lemd3	ENSMUSG00000048661
rattus_norvegicus	Lemd3	ENSRNOG00000024027
drosophila_melanogaster	MAN1	FBGN0034962
caenorhabditis_elegans		WBGENE00002275

Paralogs (2): ANKLE1 (ENSG00000160117), LEMD2 (ENSG00000161904)

Protein

Protein identifiers

Inner nuclear membrane protein Man1 — Q9Y2U8 (reviewed: Q9Y2U8)

Alternative names: LEM domain-containing protein 3

All UniProt accessions (1): Q9Y2U8

UniProt curated annotations — full annotation on UniProt →

Function. Can function as a specific repressor of TGF-beta, activin, and BMP signaling through its interaction with the R-SMAD proteins. Antagonizes TGF-beta-induced cell proliferation arrest.

Subunit / interactions. Interacts with SMAD1, SMAD2, SMAD3 and SMAD5. Binds to both phosphorylated and unphosphorylated R-SMADS.

Subcellular location. Nucleus inner membrane.

Tissue specificity. Heart, brain, placenta, lung, liver and skeletal muscle.

Disease relevance. Buschke-Ollendorff syndrome (BOS) [MIM:166700] A disease characterized by osteopoikilosis and disseminated connective-tissue nevi. Osteopoikilosis is a skeletal dysplasia characterized by a symmetric but unequal distribution of multiple hyperostotic areas in different parts of the skeleton. Elastic-type nevi (juvenile elastoma) and collagen-type nevi (dermatofibrosis lenticularis disseminata) have been described in BOS. Skin or bony lesions can be absent in some family members, whereas other relatives may have both. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (2): NP_001161086, NP_055134* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003887	LEM_dom	Domain
IPR011015	LEM/LEM-like_dom_sf	Homologous_superfamily
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR018996	Man1/Src1-like_C	Domain
IPR034394	Man1_RRM	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR041885	MAN1_winged_helix_dom	Homologous_superfamily
IPR052277	INM_ESCRT-Associated	Family

Pfam: PF03020, PF09402

UniProt features (63 total): modified residue 17, helix 10, strand 10, region of interest 6, compositionally biased region 4, turn 4, sequence variant 3, transmembrane region 2, mutagenesis site 2, initiator methionine 1, chain 1, sequence conflict 1, domain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
5ZOJ	X-RAY DIFFRACTION	2.79
5ZOK	X-RAY DIFFRACTION	2.85
2CH0	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2U8-F1	61.07	0.14

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 (17): 2, 27, 140, 141, 144, 185, 187, 209, 259, 261, 280, 352, 365, 402, 777, 883, 911

Mutagenesis-validated functional residues (2):

Position	Phenotype
703–704	impairs binding to smad1. loss of ability to repress transcriptional activation in response to tgf-beta, bmp2 and activi
835–836	impairs binding to smad1.

Function

Pathways and Gene Ontology

Reactome pathways

22 pathways

ID	Pathway
R-HSA-2980766	Nuclear Envelope Breakdown
R-HSA-2995383	Initiation of Nuclear Envelope (NE) Reformation
R-HSA-4419969	Depolymerization of the Nuclear Lamina
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013404	RAC2 GTPase cycle
R-HSA-9013405	RHOD GTPase cycle
R-HSA-9013408	RHOG GTPase cycle
R-HSA-9013423	RAC3 GTPase cycle
R-HSA-9696264	RND3 GTPase cycle
R-HSA-9696270	RND2 GTPase cycle
R-HSA-9696273	RND1 GTPase cycle
R-HSA-162582	Signal Transduction
R-HSA-1640170	Cell Cycle
R-HSA-194315	Signaling by Rho GTPases
R-HSA-2555396	Mitotic Metaphase and Anaphase
R-HSA-2995410	Nuclear Envelope (NE) Reassembly
R-HSA-68875	Mitotic Prophase
R-HSA-68882	Mitotic Anaphase
R-HSA-68886	M Phase
R-HSA-69278	Cell Cycle, Mitotic
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 348 (showing top): GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GCM_ZNF198, TATTATA_MIR374, GTGCCTT_MIR506, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, GOBP_RESPONSE_TO_TRANSFORMING_GROWTH_FACTOR_BETA, GOBP_NEGATIVE_REGULATION_OF_BMP_SIGNALING_PATHWAY, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_UP, GCM_NUMA1, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_TRANSFORMING_GROWTH_FACTOR_BETA_STIMULUS, GOBP_RESPONSE_TO_BMP, GOBP_RESPONSE_TO_GROWTH_FACTOR, GOBP_ACTIVIN_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_BMP_SIGNALING_PATHWAY

GO Biological Process (3): negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), negative regulation of BMP signaling pathway (GO:0030514), negative regulation of activin receptor signaling pathway (GO:0032926)

GO Molecular Function (4): DNA binding (GO:0003677), U1 snRNP binding (GO:1990446), nucleic acid binding (GO:0003676), protein binding (GO:0005515)

GO Cellular Component (5): nuclear inner membrane (GO:0005637), membrane (GO:0016020), nuclear membrane (GO:0031965), nucleus (GO:0005634), nuclear envelope (GO:0005635)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
RHO GTPase cycle	8
M Phase	2
Mitotic Prophase	1
Nuclear Envelope (NE) Reassembly	1
Nuclear Envelope Breakdown	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Mitotic Anaphase	1
Mitotic Metaphase and Anaphase	1
Cell Cycle, Mitotic	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	3
binding	2
nucleus	2
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
activin receptor signaling pathway	1
regulation of activin receptor signaling pathway	1
nucleic acid binding	1
snRNP binding	1
organelle inner membrane	1
nuclear membrane	1
cellular anatomical structure	1
nuclear envelope	1
organelle membrane	1
intracellular membrane-bounded organelle	1
endomembrane system	1
organelle envelope	1

Protein interactions and networks

STRING

2122 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LEMD3	BANF1	O75531	996
LEMD3	EMD	P50402	981
LEMD3	PIGN	O95427	957
LEMD3	BANF2	Q9H503	957
LEMD3	SMAD2	Q15796	949
LEMD3	LBR	Q14739	903
LEMD3	WIF1	Q9Y5W5	883
LEMD3	SMAD3	P84022	788
LEMD3	LMNB1	P20700	772
LEMD3	LMNB2	Q03252	758
LEMD3	SYNE1	Q8NF91	709
LEMD3	LMNA	P02545	687
LEMD3	SUN1	O94901	672
LEMD3	ANKLE2	Q86XL3	640
LEMD3	SUN2	Q9UH99	630

IntAct

220 interactions, top by confidence:

A	B	Type	Score
SMAD3	ZFYVE9	psi-mi:“MI:0914”(association)	0.820
SMAD1	LEMD3	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SMAD9	LEMD3	psi-mi:“MI:0915”(physical association)	0.670
LRRC32	SMPD2	psi-mi:“MI:0914”(association)	0.640
ADCY9	NEMP1	psi-mi:“MI:0914”(association)	0.640
CD27	TCAF2	psi-mi:“MI:0914”(association)	0.640
ASPH	STXBP3	psi-mi:“MI:0914”(association)	0.640
ABCD4	ABCD4	psi-mi:“MI:0914”(association)	0.640
FAM234B	ABCD4	psi-mi:“MI:0914”(association)	0.620
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
INSR	PIK3R2	psi-mi:“MI:2364”(proximity)	0.570
RABAC1	LEMD3	psi-mi:“MI:0915”(physical association)	0.560
REEP4	LEMD3	psi-mi:“MI:0915”(physical association)	0.560
SMAD2	SMAD9	psi-mi:“MI:0914”(association)	0.550
MME	TMEM223	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
SPINT2	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
ZNRF4	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
TEX29	TOR1A	psi-mi:“MI:0914”(association)	0.530
SYT12	B4GALT5	psi-mi:“MI:0914”(association)	0.530
TRHDE	MAN1A2	psi-mi:“MI:0914”(association)	0.530
AOC2	GOLGA5	psi-mi:“MI:0914”(association)	0.530

BioGRID (393): LEMD3 (Affinity Capture-MS), LEMD3 (Reconstituted Complex), LEMD3 (Affinity Capture-MS), LEMD3 (Affinity Capture-MS), LEMD3 (Affinity Capture-MS), LEMD3 (Affinity Capture-MS), LEMD3 (Affinity Capture-MS), LEMD3 (Affinity Capture-MS), LEMD3 (Affinity Capture-MS), LEMD3 (Affinity Capture-MS), LEMD3 (Affinity Capture-MS), LEMD3 (Affinity Capture-MS), LEMD3 (Affinity Capture-MS), LEMD3 (Affinity Capture-MS), LEMD3 (Affinity Capture-MS)

ESM2 similar proteins: A0A088MLT8, A2AQ25, B3KU38, B5DF41, E9PSK7, O15079, O35274, P0DPB3, P0DPB4, P12755, P49140, P85299, Q0D2I5, Q14DQ1, Q1LY51, Q3B7M3, Q3SYW5, Q4KMA0, Q4R3X1, Q50H33, Q5F3L9, Q5FVG6, Q5RD40, Q5XKK7, Q60698, Q6ZNC4, Q6ZUS6, Q6ZWB6, Q80U23, Q80U62, Q80XA6, Q812A5, Q86YI8, Q8BXL9, Q8K2W6, Q8ND83, Q8NFH8, Q8QFX1, Q8TEK3, Q924W7

Diamond homologs: A1A4K8, A1A5R1, A6NDE4, A6NEQ0, A6NFN3, A6QPR6, B0BNE4, O13845, O14369, O43251, O89086, P04147, P0C7P1, P0CB38, P0DJD3, P0DJD4, P19339, P41891, P42696, P57052, P60047, P60048, P60049, P60050, P60824, P60825, P60826, P62995, P62996, P62997, P98179, Q01081, Q03251, Q03878, Q06106, Q09511, Q10572, Q14011, Q14498, Q15415

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 211 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
VEGFR2 mediated cell proliferation	6	25.4×	7e-05
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	19.2×	1e-03
Downstream signal transduction	5	14.1×	2e-03
TGF-beta receptor signaling activates SMADs	5	12.1×	2e-03
Signaling by SCF-KIT	6	11.0×	1e-03
NCAM signaling for neurite out-growth	5	10.1×	5e-03
Signaling by BRAF and RAF1 fusions	6	7.6×	5e-03
Post-translational protein phosphorylation	7	5.2×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
monoatomic ion transmembrane transport	7	8.2×	9e-03
transforming growth factor beta receptor signaling pathway	9	8.1×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	52
Likely pathogenic	16
Uncertain significance	518
Likely benign	264
Benign	41

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068772	NM_014319.5(LEMD3):c.1363C>T (p.Gln455Ter)	Pathogenic
1068773	NM_014319.5(LEMD3):c.2203C>T (p.Arg735Ter)	Pathogenic
1073100	NM_014319.5(LEMD3):c.817dup (p.Arg273fs)	Pathogenic
1076319	NM_014319.5(LEMD3):c.934G>T (p.Gly312Ter)	Pathogenic
1414403	NM_014319.5(LEMD3):c.311del (p.Pro104fs)	Pathogenic
1453699	NM_014319.5(LEMD3):c.629del (p.Pro210fs)	Pathogenic
1455087	NM_014319.5(LEMD3):c.1558C>T (p.Gln520Ter)	Pathogenic
1458224	NM_014319.5(LEMD3):c.1323C>A (p.Tyr441Ter)	Pathogenic
1687718	NM_014319.5(LEMD3):c.2024-2A>G	Pathogenic
1699129	NM_014319.5(LEMD3):c.906del (p.Gly303fs)	Pathogenic
2697768	NM_014319.5(LEMD3):c.356_378del (p.Leu119fs)	Pathogenic
2709420	NM_014319.5(LEMD3):c.339_360del (p.Glu116fs)	Pathogenic
2726634	NM_014319.5(LEMD3):c.2106dup (p.Ile704fs)	Pathogenic
2730543	NM_014319.5(LEMD3):c.685G>T (p.Glu229Ter)	Pathogenic
2748553	NM_014319.5(LEMD3):c.2595T>G (p.Tyr865Ter)	Pathogenic
2752	NM_014319.5(LEMD3):c.457C>T (p.Gln153Ter)	Pathogenic
2753	NM_014319.5(LEMD3):c.1033_1035delinsC (p.Gly345fs)	Pathogenic
2754	NM_014319.5(LEMD3):c.1035dup (p.Cys346fs)	Pathogenic
2755	NM_014319.5(LEMD3):c.1609C>T (p.Arg537Ter)	Pathogenic
2756	LEMD3, 1941+5delG	Pathogenic
2756413	NM_014319.5(LEMD3):c.2584dup (p.Thr862fs)	Pathogenic
2757	NM_014319.5(LEMD3):c.2154dup (p.Ala719fs)	Pathogenic
2758	NM_014319.5(LEMD3):c.2564G>A (p.Trp855Ter)	Pathogenic
2759	NM_014319.5(LEMD3):c.1963C>T (p.Arg655Ter)	Pathogenic
2760	NM_014319.5(LEMD3):c.1522+1G>A	Pathogenic
2765600	NM_014319.5(LEMD3):c.1218T>G (p.Tyr406Ter)	Pathogenic
2828218	NM_014319.5(LEMD3):c.1448T>A (p.Leu483Ter)	Pathogenic
2846733	NM_014319.5(LEMD3):c.1224_1225del (p.Asn408fs)	Pathogenic
2860372	NM_014319.5(LEMD3):c.595dup (p.Ala199fs)	Pathogenic
2876086	NM_014319.5(LEMD3):c.2139_2140delinsCT (p.Lys713_Lys714delinsAsnTer)	Pathogenic

SpliceAI

2246 predictions. Top by Δscore:

Variant	Effect	Δscore
12:65210920:T:TA	acceptor_gain	1.0000
12:65210924:A:AG	acceptor_gain	1.0000
12:65210925:G:GG	acceptor_gain	1.0000
12:65210925:GT:G	acceptor_gain	1.0000
12:65210925:GTA:G	acceptor_gain	1.0000
12:65210925:GTAGA:G	acceptor_gain	1.0000
12:65210964:G:GG	donor_gain	1.0000
12:65215976:GGAAA:G	acceptor_gain	1.0000
12:65216039:TGCAG:T	donor_loss	1.0000
12:65216040:GCAGG:G	donor_loss	1.0000
12:65216041:CAG:C	donor_loss	1.0000
12:65216042:AGGTA:A	donor_loss	1.0000
12:65216043:GG:G	donor_loss	1.0000
12:65216044:G:GA	donor_loss	1.0000
12:65216045:T:A	donor_loss	1.0000
12:65218548:CCAG:C	acceptor_loss	1.0000
12:65218549:CAG:C	acceptor_loss	1.0000
12:65218550:A:AG	acceptor_gain	1.0000
12:65218551:G:GA	acceptor_loss	1.0000
12:65218551:G:GG	acceptor_gain	1.0000
12:65218551:GGA:G	acceptor_gain	1.0000
12:65218616:AAAAG:A	donor_loss	1.0000
12:65218618:AA:A	donor_gain	1.0000
12:65218618:AAGT:A	donor_loss	1.0000
12:65218619:AGTA:A	donor_loss	1.0000
12:65218620:G:GG	donor_gain	1.0000
12:65218620:GTA:G	donor_loss	1.0000
12:65218621:T:TC	donor_loss	1.0000
12:65218622:AA:A	donor_loss	1.0000
12:65238668:GGTGT:G	acceptor_gain	1.0000

AlphaMissense

5910 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:65169658:T:C	L21P	1.000
12:65169709:T:A	V38D	1.000
12:65169711:T:G	Y39D	1.000
12:65169724:T:C	L43P	1.000
12:65241075:T:A	W765R	1.000
12:65241075:T:C	W765R	1.000
12:65241076:G:C	W765S	1.000
12:65241077:G:C	W765C	1.000
12:65241077:G:T	W765C	1.000
12:65241081:G:C	G767R	1.000
12:65243390:T:C	F770L	1.000
12:65243391:T:C	F770S	1.000
12:65243391:T:G	F770C	1.000
12:65243392:T:A	F770L	1.000
12:65243392:T:G	F770L	1.000
12:65243435:T:C	C785R	1.000
12:65243436:G:A	C785Y	1.000
12:65243437:T:G	C785W	1.000
12:65243439:T:A	L786Q	1.000
12:65243439:T:C	L786P	1.000
12:65243439:T:G	L786R	1.000
12:65243441:A:G	K787E	1.000
12:65243443:G:C	K787N	1.000
12:65243443:G:T	K787N	1.000
12:65243445:T:A	I788N	1.000
12:65243445:T:C	I788T	1.000
12:65243445:T:G	I788S	1.000
12:65243447:C:G	R789G	1.000
12:65243448:G:C	R789P	1.000
12:65243448:G:T	R789L	1.000

dbSNP variants (sampled 300 via entrez): RS1000270388 (12:65174803 G>A,T), RS1000323162 (12:65218459 G>A), RS1000360706 (12:65233254 G>A), RS1000361151 (12:65206244 A>G), RS1000389956 (12:65225929 T>C), RS1000421027 (12:65226151 C>A), RS1000436494 (12:65171001 A>G), RS1000468908 (12:65183473 T>A), RS1000478547 (12:65181352 C>T), RS1000606368 (12:65173016 G>A), RS1000619036 (12:65175621 C>T), RS1000674868 (12:65223194 T>C), RS1000716410 (12:65180210 T>A,G), RS1000785624 (12:65181604 C>T), RS1000839734 (12:65186418 C>T)

Disease associations

OMIM: gene MIM:607844 | disease phenotypes: MIM:166700, MIM:123880, MIM:108010

GenCC curated gene-disease

Disease	Classification	Inheritance
Buschke-Ollendorff syndrome	Definitive	Autosomal dominant
isolated osteopoikilosis	Supportive	Autosomal dominant
melorheostosis with osteopoikilosis	Supportive	Autosomal dominant

Mondo (7): Buschke-Ollendorff syndrome (MONDO:0008157), Gorham-Stout disease (MONDO:0007414), osteopoikilosis (MONDO:0001414), melorheostosis with osteopoikilosis (MONDO:0015995), intellectual disability (MONDO:0001071), arteriovenous malformations of the brain (MONDO:0007154), isolated osteopoikilosis (MONDO:0015634)

Orphanet (5): NON RARE IN EUROPE: Buschke-Ollendorff syndrome (Orphanet:1306), Gorham-Stout disease (Orphanet:73), Melorheostosis with osteopoikilosis (Orphanet:1879), Brain arteriovenous malformation (Orphanet:46724), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

85 total (30 of 85 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000077	Abnormality of the kidney
HP:0000085	Horseshoe kidney
HP:0000086	Ectopic kidney
HP:0000089	Renal hypoplasia
HP:0000175	Cleft palate
HP:0000233	Thin vermilion border
HP:0000252	Microcephaly
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000347	Micrognathia
HP:0000426	Prominent nasal bridge
HP:0000445	Wide nose
HP:0000490	Deeply set eye
HP:0000574	Thick eyebrow
HP:0000620	Dacryocystitis
HP:0000664	Synophrys
HP:0000668	Hypodontia
HP:0000750	Delayed speech and language development
HP:0000818	Abnormality of the endocrine system
HP:0000819	Diabetes mellitus
HP:0000822	Hypertension
HP:0000951	Abnormality of the skin
HP:0000953	Hyperpigmentation of the skin
HP:0001012	Multiple lipomas
HP:0001159	Syndactyly
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001328	Specific learning disability

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST004068_7	Venous thromboembolism adjusted for sickle cell variant rs77121243-T	1.000000e-08
GCST005956_45	Waist-to-hip ratio adjusted for BMI	5.000000e-07
GCST005959_29	Waist-to-hip ratio adjusted for BMI x sex interaction	8.000000e-06
GCST006871_5	Total hippocampal volume	2.000000e-20
GCST006874_1	Hippocampal subfield CA1 volume (corrected for total hippocampal volume)	8.000000e-19
GCST006886_4	Subiculum volume	2.000000e-13
GCST006887_3	Hippocampal subfield CA1 volume	6.000000e-28
GCST006888_2	Hippocampal subfield CA3 volume	9.000000e-19
GCST006889_1	Hippocampal subfield CA4 volume	3.000000e-19
GCST006890_5	Dentate gyrus granule cell layer volume	5.000000e-21
GCST006891_4	Dentate gyrus molecular layer volume	6.000000e-17
GCST006892_1	Hippocampal fissure volume	2.000000e-13
GCST008839_61	Height	2.000000e-14
GCST010703_95	Brain morphology (MOSTest)	3.000000e-46

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008343	sex interaction measurement
EFO:0005035	hippocampal volume
EFO:0009394	hippocampal CA1 volume
EFO:0009395	hippocampal CA3 volume
EFO:0009396	hippocampal CA4 volume
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D002538	Intracranial Arteriovenous Malformations	C10.228.140.300.520; C10.500.190.500; C14.240.850.750.295; C14.240.850.875.500; C14.907.150.295; C14.907.253.560.400; C16.131.240.850.750.295; C16.131.240.850.875.500; C16.131.666.190.500
D010023	Osteopoikilosis	C05.116.099.708.702.685; C17.300.705
C537415	Buschke-Ollendorff syndrome (supp.)
C563593	Melorheostosis with Osteopoikilosis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	2
Valproic Acid	affects expression, decreases expression	2
FR900359	affects phosphorylation	1
dicrotophos	decreases expression	1
arsenite	affects binding, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
ICG 001	decreases expression	1
jinfukang	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	increases abundance, decreases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	affects phosphorylation	1
Cisplatin	decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Phthalic Acids	decreases methylation	1
Tobacco Smoke Pollution	increases expression	1
Zinc	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT01758211	PHASE3	UNKNOWN	Functional Magnetic Resonance Imagine(fMRI)Navigation in Intracranial Arteriovenous Malformation Surgery
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT04297033	PHASE2	UNKNOWN	Lovastatin for Treatment of Brain Arteriovenous Malformations
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT02314377	PHASE1	COMPLETED	Bevacizumab Therapy for Brain Arteriovenous Malformation
NCT05724745	Not specified	RECRUITING	Evaluation of 3D Magnetic Resonance Spirometry: Comparison with Spirometry in Healthy Subjects and Patients with Respiratory Pathologies (asthma, COPD, Bilateral Lung Transplant)
NCT02399527	Not specified	RECRUITING	Lymphatic Anomalies Registry for the Assessment of Outcome Data
NCT02744027	Not specified	COMPLETED	Imaging of Lymphatic Anomalies
NCT03001180	Not specified	RECRUITING	Identification of Biomarkers for Patients with Vascular Anomalies
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients