LFNG

protein-coding

LFNG O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase, the group of Beta 3-glycosyltransferases|MicroRNA protein coding host genes

Gene summary

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. [provided by RefSeq, May 2018]

MANE transcript

NM_001040167.2

Inheritance

ClinVar variants

P:10U:123B:103

Top phenotype

Spondylocostal dysostosis 3, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.3

Max pathogenic AF

—

Genomic locus

chr7:2,512,529-2,529,177

External References & Databases

Ensembl (ENSG00000106003)

Transcript & Mutation Effects

hg38 • Region Span ~16.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive spondylocostal dysostosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010180

Submitter: Orphanet

spondylocostal dysostosis 3, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012349

Submitter: PanelApp Australia

spondylocostal dysostosis 3, autosomal recessiveDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012349

Submitter: G2P

spondylocostal dysostosis 3, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012349

Submitter: Labcorp Genetics (formerly Invitae)

spondylocostal dysostosis 3, autosomal recessiveMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012349

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Spondylocostal dysostosis 3, autosomal recessiveAR

Manifestation: Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 16385447; 20301771

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LFNG variants in ClinVar

7 Conditions Cataloged

Spondylocostal dysostosis 3, autosomal recessiveTotal: 233

Inborn genetic diseasesTotal: 59

not providedTotal: 32

not specifiedTotal: 28

LFNG-related disorderTotal: 11

LFNG-related disordersTotal: 3

Spondylocostal dysostosis 2, autosomal recessiveTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001040167.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	92 clinvar	1 clinvar	96
missense	2 clinvar	1 clinvar	116 clinvar	9 clinvar	1 clinvar	129
nonsense						0
start loss						0
frameshift	3 clinvar	2 clinvar				5
splice donor/acceptor (+/-2bp)		2 clinvar	4 clinvar			6
Total	5	5	123	101	2	236

Highest pathogenic variant AF is 0.0000054762936

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001040167.2	RefSeq	NP_001035257.1	8	MANE Select
ENST00000222725.10	Ensembl	ENSP00000222725.5	8	MANE Select
NM_001040168.2	RefSeq	NP_001035258.1	8	Standard
NM_001166355.2	RefSeq	NP_001159827.1	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
lfng	Danio rerio	Structure: CiD Quality: increased amount abnormal

Gene / Model

Organism

Observed Phenotype

lfng

Danio rerio

Structure: CiD

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Other types of O-glycan biosynthesis - Homo sapiens (human)
Notch signaling pathway - Homo sapiens (human)
Human papillomavirus infection - Homo sapiens (human)
NOTCH-Ncore
Notch Signaling Pathway

Biological Process

ovarian follicle development
somitogenesis
marginal zone B cell differentiation
compartment pattern specification
regulation of Notch signaling pathway

Molecular Function

molecular_function
acetylglucosaminyltransferase activity
O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase activity
metal ion binding

Cellular Component

extracellular region
integral component of Golgi membrane
extracellular vesicle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000222725
Coding exons: 8
Length: 16649
Individuals with no LoFs: 125369
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125376
p: 0.0000279

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.616	172	196	0.876	0.0000140	2380
Missense (PolyPhen)		38	77.38	0.49108		805
Synonymous	-1.32	105	89.1	1.18	0.00000694	829
Loss of Function	2.36	4	13.3	0.302	5.75e-7	151

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000064	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000097	0.000092	rare
European (Non-Finnish)	0.000029	0.000027	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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 (By similarity). Decreases the binding of JAG1 to NOTCH2 but not that of DLL1 (PubMed:11346656). Essential mediator of somite segmentation and patterning (By similarity). {ECO:0000250|UniProtKB:O09010, ECO:0000269|PubMed:11346656}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:16385447}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.189

Intolerance Scores

LoFtool: 0.907
RVIS EVS: -0.05
RVIS percentile EVS: 50.34

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.685

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium