EFNB1

protein-coding

ephrin B1, the group of Ephrins

Gene summary

The protein encoded by this gene is a type I membrane protein and a ligand of Eph-related receptor tyrosine kinases. It may play a role in cell adhesion and function in the development or maintenance of the nervous system. [provided by RefSeq, Jul 2008]

Previous symbols:

EPLG2
CFNS

MANE transcript

NM_004429.5

Inheritance

ClinVar variants

P:79U:108B:30

Top phenotype

Craniofrontonasal dysplasia

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:68,829,021-68,842,160

External References & Databases

Ensembl (ENSG00000090776)

Transcript & Mutation Effects

hg38 • Region Span ~13.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

craniofrontonasal syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010570

Submitter: Genomics England PanelApp

craniofrontonasal syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010570

Submitter: ClinGen

EFNB1 was first associated with X-linked craniofrontonasal syndrome as early as 2004 (Wieland et al., PMID: 15124102; Twigg et al., PMID: 15166289). The classical features of this disorder include coronal synostosis, hypertelorism, splitting of the nails, clefting of the nasal tip, and other skeletal anomalies, although a range of phenotypes including non-syndromic craniosynostoses have been observed in probands with variants in EFNB1. Craniofrontonasal syndrome is generally more severe in heterozygous females than in hemizygous males; however, mosaic males with severe phenotypes have been reported. More than 115 unique variants (including missense, nonsense, frameshift, splice site, and multi-exon deletions) in EFNB1 have been seen in humans. This curation includes 13 probands to reach the maximum score for genetic evidence (PMIDs: 15166289, 16639408, 17300690, 15124102, 15959873, 27884935, 29215649, 30651579, 23335590). The mechanism of disease is cellular interference (PMID: 23335590). This gene-disease association is supported by mouse models and expression studies (PMID: 15166289, 12919674, 15037550, 20844017). In summary, EFNB1 is definitively associated with X-linked craniofrontonasal syndrome. This curation was approved by the Craniofacial Malformations Gene Curation Expert Panel on 9/28/20.

craniofrontonasal syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010570

Submitter: Orphanet

craniofrontonasal syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010570

Submitter: Labcorp Genetics (formerly Invitae)

craniofrontonasal syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010570

Submitter: G2P

craniofrontonasal syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010570

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Craniofrontonasal dysplasiaXL

Manifestation: Craniofacial; 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: 15166289; 15124102; 15959873; 16639408; 17941886; 18627045; 20734337; 21385071; 23509643

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EFNB1 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 125

Craniofrontonasal syndromeTotal: 50

Inborn genetic diseasesTotal: 44

EFNB1-related disorderTotal: 12

not specifiedTotal: 7

EFNB1-related disordersTotal: 6

Common craniosynostosis syndromesTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004429.5. 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	1 clinvar		3 clinvar	24 clinvar		28
missense	9 clinvar	23 clinvar	99 clinvar	4 clinvar	2 clinvar	137
nonsense	14 clinvar	3 clinvar	1 clinvar			18
start loss	1 clinvar					1
frameshift	15 clinvar	6 clinvar	2 clinvar			23
splice donor/acceptor (+/-2bp)	3 clinvar	4 clinvar	3 clinvar			10
Total	43	36	108	28	2	217

Highest pathogenic variant AF is 9.1527403e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004429.5	RefSeq	NP_004420.1	5	MANE Select
ENST00000204961.5	Ensembl	ENSP00000204961.4	5	MANE Select
ENST00000851101.1	Ensembl	ENSP00000521160.1	4	Standard
ENST00000851101.2	Ensembl	ENSP00000521160.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
efnb1	Danio rerio	Structure: hepatoblast Quality: anterior orientation abnormal

Gene / Model

Organism

Observed Phenotype

efnb1

Danio rerio

Structure: hepatoblast

Quality: anterior orientation

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Axon guidance - Homo sapiens (human)
Developmental Biology
EPH-Ephrin signaling
Ephrin signaling
Ephrin B reverse signaling

Biological Process

neural crest cell migration
cell adhesion
cell-cell signaling
axon guidance
embryonic pattern specification

Molecular Function

protein tyrosine kinase activity
protein binding
ephrin receptor binding

Cellular Component

nucleus
cytoplasm
plasma membrane
integral component of plasma membrane
membrane raft

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000204961
Coding exons: 5
Length: 13151
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.59	100	156	0.641	0.0000132	2241
Missense (PolyPhen)		31	64.037	0.4841		934
Synonymous	0.263	65	67.8	0.959	0.00000584	712
Loss of Function	2.71	0	8.58	0.00	6.16e-7	148

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binds to the receptor tyrosine kinases EPHB1 and EPHA1. Binds to, and induce the collapse of, commissural axons/growth cones in vitro. May play a role in constraining the orientation of longitudinally projecting axons (By similarity). {ECO:0000250}.;
Disease: DISEASE: Craniofrontonasal syndrome (CFNS) [MIM:304110]: X-linked inherited syndrome characterized by hypertelorism, coronal synostosis with brachycephaly, downslanting palpebral fissures, clefting of the nasal tip, joint anomalies, longitudinally grooved fingernails and other digital anomalies. {ECO:0000269|PubMed:15124102, ECO:0000269|PubMed:15166289, ECO:0000269|PubMed:15959873}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.371

Intolerance Scores

RVIS EVS: 0.22
RVIS percentile EVS: 68.13

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.862

Gene Damage Prediction

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