LFNG

Summary

LFNG (LFNG O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase, HGNC:6560) is a protein-coding gene on chromosome 7p22.3, encoding Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe (Q8NES3). Glycosyltransferase that initiates the elongation of O-linked fucose residues attached to EGF-like repeats in the extracellular domain of Notch molecules.

This gene is a member of the glycosyltransferase 31 gene family. Members of this gene family, which also includes the MFNG (GeneID: 4242) and RFNG (GeneID: 5986) genes, encode evolutionarily conserved glycosyltransferases that act in the Notch signaling pathway to define boundaries during embryonic development. While their genomic structure is distinct from other glycosyltransferases, these proteins have a fucose-specific beta-1,3-N-acetylglucosaminyltransferase activity that leads to elongation of O-linked fucose residues on Notch, which alters Notch signaling. The protein encoded by this gene is predicted to be a single-pass type II Golgi membrane protein but it may also be secreted and proteolytically processed like the related proteins in mouse and Drosophila (PMID: 9187150). Mutations in this gene have been associated with autosomal recessive spondylocostal dysostosis 3.

Source: NCBI Gene 3955 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spondylocostal dysostosis 3, autosomal recessive (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 8
• Clinical variants (ClinVar): 331 total — 6 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 44
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_001040167

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6560
Approved symbol	LFNG
Name	LFNG O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase
Location	7p22.3
Locus type	gene with protein product
Status	Approved
Aliases	SCDO3
Ensembl gene	ENSG00000106003
Ensembl biotype	protein_coding
OMIM	602576
Entrez	3955

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 retained_intron

ENST00000222725, ENST00000338732, ENST00000359574, ENST00000402045, ENST00000402506, ENST00000493850

RefSeq mRNA: 4 — MANE Select: NM_001040167 NM_001040167, NM_001040168, NM_001166355, NM_002304

CCDS: CCDS34586, CCDS34587, CCDS55081, CCDS55082

Canonical transcript exons

ENST00000222725 — 8 exons

Exon	Start	End
ENSE00000667281	2525219	2525318
ENSE00000667282	2525414	2525567
ENSE00000667286	2526836	2526921
ENSE00001329541	2519774	2520293
ENSE00001556361	2527146	2528429
ENSE00003538047	2526244	2526409
ENSE00003552934	2524695	2524743
ENSE00003558119	2525685	2525770

Expression profiles

Bgee: expression breadth ubiquitous, 167 present calls, max score 98.36.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 67.1231 / max 3820.1019, expressed in 1635 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76977	65.8860	1634
76979	1.0759	326
76976	0.0891	31
76978	0.0721	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.36	gold quality
body of pancreas	UBERON:0001150	95.39	gold quality
monocyte	CL:0000576	94.75	gold quality
leukocyte	CL:0000738	94.63	gold quality
mononuclear cell	CL:0000842	94.34	gold quality
mucosa of transverse colon	UBERON:0004991	93.13	gold quality
skin of abdomen	UBERON:0001416	90.96	gold quality
skin of leg	UBERON:0001511	89.99	gold quality
ventricular zone	UBERON:0003053	89.24	gold quality
transverse colon	UBERON:0001157	87.06	gold quality
body of stomach	UBERON:0001161	86.59	gold quality
minor salivary gland	UBERON:0001830	86.34	gold quality
zone of skin	UBERON:0000014	85.01	gold quality
small intestine Peyer’s patch	UBERON:0003454	83.42	gold quality
stomach	UBERON:0000945	83.32	gold quality
pancreas	UBERON:0001264	83.32	gold quality
omental fat pad	UBERON:0010414	83.19	gold quality
peritoneum	UBERON:0002358	83.11	gold quality
nucleus accumbens	UBERON:0001882	83.06	gold quality
apex of heart	UBERON:0002098	82.91	gold quality
gall bladder	UBERON:0002110	82.77	gold quality
spleen	UBERON:0002106	82.68	gold quality
sural nerve	UBERON:0015488	82.20	gold quality
right lung	UBERON:0002167	82.15	gold quality
saliva-secreting gland	UBERON:0001044	82.11	gold quality
upper lobe of left lung	UBERON:0008952	81.50	gold quality
rectum	UBERON:0001052	81.40	gold quality
mouth mucosa	UBERON:0003729	81.38	gold quality
blood	UBERON:0000178	81.35	gold quality
adipose tissue of abdominal region	UBERON:0007808	80.93	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.26

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MESP2, NOTCH1, RBPJ

miRNA regulators (miRDB)

50 targeting LFNG, 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-8485	100.00	77.57	4731
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-4762-3P	99.43	69.72	2363
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-3150B-3P	98.81	67.21	1728
HSA-MIR-6846-5P	98.81	65.86	1121

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 11)

• Mutation of the LFNG gene causes spondylocostal dysostosis with a severe vertebral phenotype, reinforcing the hypothesis that proper regulation of the Notch signaling pathway is an absolute requirement for the correct patterning of the axial skeleton. (PMID:16385447)
• Reduced LFNG expression facilitates JAG/NOTCH luminal progenitor signaling and cooperates with MET/CAVEOLIN basal-type signaling to promote basal-like breast cancer. (PMID:22624713)
• LFNG expression correlates with expansion of cancer stem cell populations and NKX3.1 expression in human prostate cancer. (PMID:24709423)
• a potent tumor-suppressive function for Lfng (PMID:26279302)
• TGFBR2 signaling can affect Notch1 glycosylation via regulation of glycosyltransferase LFNG expression and provide a first mechanistic example for altered glycosylation in microsatellite instability colorectal tumor cells. (PMID:27156840)
• Genetic interaction between lunatic fringe and TP53 was identified in breast cancer tumorigenesis. (PMID:28938159)
• LFNG expression plays a functional role in regulating melanoma metastasis. (PMID:29193607)
• LFNG mutation is associated with spondylocostal dysostosis. (PMID:30531807)
• Bioinformatics and Functional Analyses Implicate Potential Roles for EOGT and L-fringe in Pancreatic Cancers. (PMID:33562410)
• Lunatic fringe promotes the aggregation of CADASIL NOTCH3 mutant proteins. (PMID:33894418)
• Identification of bi-allelic LFNG variants in three patients and further clinical and molecular refinement of spondylocostal dysostosis 3. (PMID:37038048)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	lfng	ENSDARG00000037879
mus_musculus	Lfng	ENSMUSG00000029570
rattus_norvegicus	Lfng	ENSRNOG00000001250
drosophila_melanogaster	fng	FBGN0011591

Paralogs (3): MFNG (ENSG00000100060), RFNG (ENSG00000169733), B3GLCT (ENSG00000187676)

Protein

Protein identifiers

Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe — Q8NES3 (reviewed: Q8NES3)

Alternative names: O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase

All UniProt accessions (1): Q8NES3

UniProt curated annotations — full annotation on UniProt →

Function. Glycosyltransferase that initiates the elongation of O-linked fucose residues attached to EGF-like repeats in the extracellular domain of Notch molecules. Modulates NOTCH1 activity by modifying O-fucose residues at specific EGF-like domains resulting in inhibition of NOTCH1 activation by JAG1 and enhancement of NOTCH1 activation by DLL1 via an increase in its binding to DLL1. Decreases the binding of JAG1 to NOTCH2 but not that of DLL1. Essential mediator of somite segmentation and patterning.

Subcellular location. Golgi apparatus. Golgi apparatus membrane.

Post-translational modifications. A soluble form may be derived from the membrane form by proteolytic processing.

Disease relevance. Spondylocostal dysostosis 3, autosomal recessive (SCDO3) [MIM:609813] A condition of variable severity associated with vertebral and rib segmentation defects. The main skeletal malformations include fusion of vertebrae, hemivertebrae, fusion of certain ribs, and other rib malformations. Deformity of the chest and spine (severe scoliosis, kyphoscoliosis and lordosis) is a natural consequence of the malformation and leads to a dwarf-like appearance. As the thorax is small, infants frequently have respiratory insufficiency and repeated respiratory infections resulting in life-threatening complications in the first year of life. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Manganese is the most effective. Can also use cobalt with lower efficiency. Has some activity with magnesium and calcium, but not zinc.

Similarity. Belongs to the glycosyltransferase 31 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8NES3-1	1	yes
Q8NES3-2	2
Q8NES3-3	3
Q8NES3-4	4

RefSeq proteins (4): NP_001035257, NP_001035258, NP_001159827, NP_002295 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003378	Fringe-like_glycosylTrfase	Domain
IPR017374	Fringe	Family

Pfam: PF02434

Enzyme classification (BRENDA):

• EC 2.4.1.222 — O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase (BRENDA: 8 organisms, 66 substrates, 5 inhibitors, 20 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
P-NITROPHENYL-ALPHA-L-FUCOSE	0.0012–0.129	15
UDP-BETA-D-GLCNAC	0.0343–0.0707	5

Catalyzed reactions (Rhea), 2 shown:

• 3-O-(alpha-L-fucosyl)-L-seryl-[EGF-like domain protein] + UDP-N-acetyl-alpha-D-glucosamine = 3-O-(N-acetyl-beta-D-glucosaminyl-(1->3)-alpha-L-fucosyl)-L-seryl-[EGF-like domain protein] + UDP + H(+) (RHEA:70511)
• 3-O-(alpha-L-fucosyl)-L-threonyl-[EGF-like domain protein] + UDP-N-acetyl-alpha-D-glucosamine = 3-O-(N-acetyl-beta-D-glucosaminyl-(1->3)-alpha-L-fucosyl)-L-threonyl-[EGF-like domain protein] + UDP + H(+) (RHEA:70531)

UniProt features (29 total): splice variant 6, sequence variant 4, sequence conflict 4, binding site 4, disulfide bond 3, topological domain 2, chain 1, site 1, glycosylation site 1, transmembrane region 1, region of interest 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NES3-F1	83.66	0.67

Functional residue map

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

Catalytic / active sites (2): 86–87 (cleavage; by furin-like protease); 290

Ligand- & substrate-binding residues (4): 129; 201; 202; 314

Disulfide bonds (3): 168–179, 197–260, 364–373

Glycosylation sites (1): 167

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-1912420	Pre-NOTCH Processing in Golgi
R-HSA-5083630	Defective LFNG causes SCDO3
R-HSA-9824272	Somitogenesis
R-HSA-9831926	Nephron development
R-HSA-1266738	Developmental Biology
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-1912422	Pre-NOTCH Expression and Processing
R-HSA-3781865	Diseases of glycosylation
R-HSA-3906995	Diseases associated with O-glycosylation of proteins
R-HSA-5668914	Diseases of metabolism
R-HSA-9758941	Gastrulation
R-HSA-9793380	Formation of paraxial mesoderm
R-HSA-9830369	Kidney development

MSigDB gene sets: 400 (showing top): REACTOME_SIGNALING_BY_NOTCH, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_B_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_NOTCH_SIGNALING_PATHWAY, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, GOBP_REGULATION_OF_MEIOTIC_CELL_CYCLE, CHANDRAN_METASTASIS_DN, GOBP_NEGATIVE_REGULATION_OF_NOTCH_SIGNALING_PATHWAY, chr7p22, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_MEIOTIC_CELL_CYCLE, GOBP_ANIMAL_ORGAN_MORPHOGENESIS

GO Biological Process (12): ovarian follicle development (GO:0001541), somitogenesis (GO:0001756), marginal zone B cell differentiation (GO:0002315), compartment pattern specification (GO:0007386), regulation of Notch signaling pathway (GO:0008593), animal organ morphogenesis (GO:0009887), regulation of somitogenesis (GO:0014807), T cell differentiation (GO:0030217), positive regulation of Notch signaling pathway (GO:0045747), positive regulation of meiotic cell cycle (GO:0051446), obsolete negative regulation of Notch signaling pathway involved in somitogenesis (GO:1902367), pattern specification process (GO:0007389)

GO Molecular Function (4): O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase activity (GO:0033829), metal ion binding (GO:0046872), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757)

GO Cellular Component (5): Golgi membrane (GO:0000139), extracellular region (GO:0005576), extracellular vesicle (GO:1903561), Golgi apparatus (GO:0005794), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Developmental Biology	2
Pre-NOTCH Expression and Processing	1
Diseases associated with O-glycosylation of proteins	1
Formation of paraxial mesoderm	1
Kidney development	1
Signal Transduction	1
Signaling by NOTCH	1
Diseases of metabolism	1
Diseases of glycosylation	1
Disease	1
Gastrulation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anterior/posterior pattern specification	2
Notch signaling pathway	2
cellular anatomical structure	2
female gonad development	1
anatomical structure development	1
segmentation	1
chordate embryonic development	1
anatomical structure formation involved in morphogenesis	1
somite development	1
mature B cell differentiation involved in immune response	1
regulation of signal transduction	1
anatomical structure morphogenesis	1
animal organ development	1
somitogenesis	1
regulation of anatomical structure morphogenesis	1
regulation of multicellular organismal process	1
lymphocyte differentiation	1
T cell activation	1
regulation of Notch signaling pathway	1
positive regulation of signal transduction	1
positive regulation of cell cycle	1
meiotic cell cycle	1
regulation of meiotic cell cycle	1
positive regulation of reproductive process	1
multicellular organism development	1
multicellular organismal process	1
acetylglucosaminyltransferase activity	1
cation binding	1
catalytic activity	1
transferase activity	1
Golgi apparatus	1
bounding membrane of organelle	1
extracellular region	1
vesicle	1
extracellular membrane-bounded organelle	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

816 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LFNG	MESP2	Q0VG99	926
LFNG	DLL1	O00548	892
LFNG	DLL3	Q9NYJ7	843
LFNG	NOTCH2	Q04721	785
LFNG	HES5	Q5TA89	769
LFNG	JAG1	P78504	765
LFNG	POFUT1	Q9H488	755
LFNG	TBX6	O95947	744
LFNG	NOTCH1	P46531	713
LFNG	NRARP	Q7Z6K4	694
LFNG	NOTCH3	Q9UM47	671
LFNG	HEY1	Q9Y5J3	670
LFNG	TCF15	Q12870	623
LFNG	RBPJ	Q06330	622
LFNG	MESP1	Q9BRJ9	589

IntAct

6 interactions, top by confidence:

A	B	Type	Score
LFNG	HSPA8	psi-mi:“MI:0914”(association)	0.350
C1orf54	QSOX1	psi-mi:“MI:0914”(association)	0.350
LCN6	HIGD1C	psi-mi:“MI:0914”(association)	0.350
MMP3	VGF	psi-mi:“MI:0914”(association)	0.350
PRG3	IGLL5	psi-mi:“MI:0914”(association)	0.350

BioGRID (13): CCT7 (Affinity Capture-MS), CCT2 (Affinity Capture-MS), CCT6A (Affinity Capture-MS), CCT3 (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), CCT6A (Affinity Capture-MS), TCP1 (Affinity Capture-MS), CCT6B (Affinity Capture-MS), WRAP73 (Affinity Capture-MS), CCT7 (Affinity Capture-MS), CCT4 (Affinity Capture-MS), CCT2 (Affinity Capture-MS), APP (Reconstituted Complex)

ESM2 similar proteins: A5D7I4, A5PK45, A7MB73, A9X1C8, O09009, O09010, O12971, O12972, O60568, O97583, P16442, P52848, P52849, P52850, P97464, Q02353, Q16394, Q2KJ92, Q3UHN9, Q5IGR7, Q5IGR8, Q5R6K5, Q5RBC3, Q5T4B2, Q5U367, Q5U4X8, Q6GQK9, Q6IS24, Q6ZQ11, Q6ZRP7, Q7Z4H8, Q812F8, Q86X52, Q8K297, Q8NBJ5, Q8NES3, Q8R087, Q8VHI3, Q924T4, Q9EQH7

Diamond homologs: O00587, O09008, O09009, O09010, O12971, O12972, P79948, P79949, Q24342, Q2KJ92, Q5IS64, Q5YB40, Q6KFX9, Q8JHF2, Q8NES3, Q924T4, Q9R1U9, Q9Y644, Q9YHB3, Q5F3G7

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
LFNG	up-regulates	DLL1	binding
LFNG	up-regulates	NOTCH2	binding
LFNG	down-regulates	NOTCH2	binding
LFNG	down-regulates	JAG1	binding
NOTCH1	“up-regulates quantity by expression”	LFNG	“transcriptional regulation”
NOTCH	“up-regulates quantity by expression”	LFNG	“transcriptional regulation”
LFNG	up-regulates	DLL3	binding
LFNG	up-regulates	NOTCH1	binding
LFNG	up-regulates	NOTCH1	glycosylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	4
Uncertain significance	125
Likely benign	143
Benign	31

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1976681	NM_001040167.2(LFNG):c.443dup (p.Thr149fs)	Pathogenic
2035397	NM_001040167.2(LFNG):c.216_217del (p.His72fs)	Pathogenic
4819703	NM_001166355.2(LFNG):c.55C>T (p.Gln19Ter)	Pathogenic
619139	NM_001040167.2(LFNG):c.601G>A (p.Asp201Asn)	Pathogenic
619140	NM_001040167.2(LFNG):c.372del (p.Lys124fs)	Pathogenic
6999	NM_001040167.2(LFNG):c.564C>A (p.Phe188Leu)	Pathogenic
3220895	NM_001040167.2(LFNG):c.434C>T (p.Thr145Met)	Likely pathogenic
3377130	NM_001040167.2(LFNG):c.736-2A>G	Likely pathogenic
3638207	NM_001040167.2(LFNG):c.987+1G>A	Likely pathogenic
4845695	NM_001166355.2(LFNG):c.159_166dup (p.Glu56fs)	Likely pathogenic

SpliceAI

955 predictions. Top by Δscore:

Variant	Effect	Δscore
7:2520290:GATG:G	donor_gain	1.0000
7:2524694:GAC:G	acceptor_gain	1.0000
7:2524742:GG:G	donor_gain	1.0000
7:2524743:GG:G	donor_gain	1.0000
7:2524743:GGT:G	donor_loss	1.0000
7:2524744:G:A	donor_loss	1.0000
7:2524744:G:GG	donor_gain	1.0000
7:2524745:T:A	donor_loss	1.0000
7:2525216:CAGG:C	acceptor_loss	1.0000
7:2525217:A:AC	acceptor_loss	1.0000
7:2525217:A:AG	acceptor_gain	1.0000
7:2525217:AG:A	acceptor_gain	1.0000
7:2525218:G:GA	acceptor_gain	1.0000
7:2525218:GG:G	acceptor_gain	1.0000
7:2525218:GGC:G	acceptor_gain	1.0000
7:2525218:GGCA:G	acceptor_gain	1.0000
7:2525218:GGCAA:G	acceptor_gain	1.0000
7:2525315:GGAA:G	donor_gain	1.0000
7:2525316:G:GT	donor_gain	1.0000
7:2525316:GAA:G	donor_gain	1.0000
7:2525318:AG:A	donor_loss	1.0000
7:2525319:G:GG	donor_gain	1.0000
7:2525319:GTG:G	donor_loss	1.0000
7:2525408:CCTCA:C	acceptor_loss	1.0000
7:2525409:CTCAG:C	acceptor_loss	1.0000
7:2525410:TCAGG:T	acceptor_loss	1.0000
7:2525411:CAGGT:C	acceptor_loss	1.0000
7:2525412:AGG:A	acceptor_loss	1.0000
7:2525412:AGGT:A	acceptor_gain	1.0000
7:2525413:G:GA	acceptor_loss	1.0000

AlphaMissense

2444 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:2520223:C:T	T121I	1.000
7:2525431:A:T	D200V	1.000
7:2525433:G:C	D201H	1.000
7:2525434:A:T	D201V	1.000
7:2525437:A:C	D202A	1.000
7:2525437:A:T	D202V	1.000
7:2525703:T:C	F252L	1.000
7:2525705:T:A	F252L	1.000
7:2525705:T:G	F252L	1.000
7:2525729:C:G	C260W	1.000
7:2526287:G:C	D289H	1.000
7:2526291:A:C	D290A	1.000
7:2526291:A:G	D290G	1.000
7:2526291:A:T	D290V	1.000
7:2526295:C:G	C291W	1.000
7:2520217:T:A	V119D	0.999
7:2520221:G:C	K120N	0.999
7:2520221:G:T	K120N	0.999
7:2520234:T:C	F125L	0.999
7:2520236:C:A	F125L	0.999
7:2520236:C:G	F125L	0.999
7:2520270:T:A	W137R	0.999
7:2520270:T:C	W137R	0.999
7:2525239:T:A	C168S	0.999
7:2525240:G:A	C168Y	0.999
7:2525240:G:C	C168S	0.999
7:2525241:C:G	C168W	0.999
7:2525272:T:A	C179S	0.999
7:2525273:G:C	C179S	0.999
7:2525277:G:C	K180N	0.999

dbSNP variants (sampled 300 via entrez): RS1000217004 (7:2510685 G>T), RS1000649498 (7:2511230 A>G), RS1000715770 (7:2510528 T>G), RS1000768182 (7:2526428 C>A), RS1000798907 (7:2513443 C>G,T), RS1001020217 (7:2511116 C>G,T), RS1001027735 (7:2524914 A>G), RS1001272010 (7:2521169 T>C), RS1001409623 (7:2514520 A>T), RS1001530160 (7:2529551 C>T), RS1001538978 (7:2519407 C>T), RS1001773482 (7:2527082 T>A,C), RS1001842603 (7:2514296 C>T), RS1001897517 (7:2526933 C>G), RS1002262411 (7:2529643 G>A)

Disease associations

OMIM: gene MIM:602576 | disease phenotypes: MIM:609813, MIM:608681

GenCC curated gene-disease

Disease	Classification	Inheritance
spondylocostal dysostosis 3, autosomal recessive	Definitive	Autosomal recessive
autosomal recessive spondylocostal dysostosis	Supportive	Autosomal recessive

Mondo (3): spondylocostal dysostosis 3, autosomal recessive (MONDO:0012349), spondylocostal dysostosis 2, autosomal recessive (MONDO:0012097), autosomal recessive spondylocostal dysostosis (MONDO:0010180)

Orphanet (1): Autosomal recessive spondylocostal dysostosis (Orphanet:2311)

HPO phenotypes

44 total (30 of 44 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000069	Abnormality of the ureter
HP:0000175	Cleft palate
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000269	Prominent occiput
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000358	Posteriorly rotated ears
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000772	Abnormal rib morphology
HP:0000776	Congenital diaphragmatic hernia
HP:0000902	Rib fusion
HP:0001238	Slender finger
HP:0001249	Intellectual disability
HP:0001511	Intrauterine growth retardation
HP:0001537	Umbilical hernia
HP:0002093	Respiratory insufficiency
HP:0002435	Meningocele
HP:0002650	Scoliosis
HP:0002808	Kyphosis
HP:0003298	Spina bifida occulta
HP:0003311	Hypoplasia of the odontoid process
HP:0003312	Abnormal form of the vertebral bodies
HP:0003422	Vertebral segmentation defect

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST003262_847	Post bronchodilator FEV1	1.000000e-06
GCST003264_876	Post bronchodilator FEV1/FVC ratio	1.000000e-06
GCST004777_15	Diastolic blood pressure	1.000000e-06
GCST006258_9	Diastolic blood pressure	3.000000e-11
GCST006259_39	Systolic blood pressure	1.000000e-10
GCST007929_77	Medication use (calcium channel blockers)	1.000000e-08
GCST007930_9	Medication use (agents acting on the renin-angiotensin system)	5.000000e-10
GCST90002395_497	Mean platelet volume	4.000000e-10

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume
EFO:0004713	FEV/FVC ratio
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0009930	Calcium channel blocker use measurement
EFO:0009931	Agents acting on the renin-angiotensin system use measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535781	Spondylocostal dysostosis, autosomal recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, increases methylation	6
Estradiol	affects cotreatment, decreases expression, increases expression	5
trichostatin A	affects cotreatment, decreases expression	3
Benzo(a)pyrene	affects methylation, increases expression	3
sodium arsenite	affects methylation, decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
Calcitriol	decreases expression, affects cotreatment	2
Cisplatin	affects cotreatment, increases expression, affects expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
OTX015	increases expression	1
bisphenol F	affects cotreatment, increases expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	increases expression	1
propionaldehyde	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
beta-lapachone	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	increases expression	1
tobacco tar	decreases expression	1
benzo(e)pyrene	decreases methylation	1
ferrous chloride	decreases expression	1
propionic acid	increases expression	1
aflatoxin B2	decreases methylation	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A3U1	SEES3-1V human LFNG, clone1	Embryonic stem cell	Male
CVCL_A3U2	SEES3-1V human LFNG, clone2	Embryonic stem cell	Male
CVCL_A3U3	SEES3-1V human LFNG, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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