EFS

Summary

EFS (embryonal Fyn-associated substrate, HGNC:16898) is a protein-coding gene on chromosome 14q11.2, encoding Embryonal Fyn-associated substrate (O43281). Docking protein which plays a central coordinating role for tyrosine-kinase-based signaling related to cell adhesion.

The protein encoded by this gene is a member of the CAS (CRK-associated substrate) family of adaptor proteins which typically serve as scaffolds for the assembly of larger signaling complexes. These complexes form at the cell surface where integrin binding leads to the subsequent phosphorylation of a CAS protein. Additional binding of SRC family kinases leads to CAS hyperphosphorylation and the creation of binding sites for CRK and other proteins that cause actin cytoskeleton reorganization. This gene plays a role in integrin-mediated cell attachment, spreading, and migration and also plays a role in both normal and malignant cellular transformation. This broadly expressed gene has been shown to play a role in neurite outgrowth and its expression in the thymus and lymphocytes is important for T cell maturation and the development of immunological self-tolerance. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 10278 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 101 total
• MANE Select transcript: NM_005864

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16898
Approved symbol	EFS
Name	embryonal Fyn-associated substrate
Location	14q11.2
Locus type	gene with protein product
Status	Approved
Aliases	EFS2, EFS1, HEFS, SIN, CASS3
Ensembl gene	ENSG00000100842
Ensembl biotype	protein_coding
OMIM	609906
Entrez	10278

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000216733, ENST00000351354, ENST00000429593, ENST00000923553, ENST00000963506

RefSeq mRNA: 4 — MANE Select: NM_005864 NM_001277174, NM_001385607, NM_005864, NM_032459

CCDS: CCDS61404, CCDS9595, CCDS9596

Canonical transcript exons

ENST00000216733 — 6 exons

Exon	Start	End
ENSE00000653939	23358876	23358965
ENSE00000653940	23359317	23360039
ENSE00000889221	23360555	23360833
ENSE00001379666	23360141	23360281
ENSE00001951774	23356406	23357660
ENSE00003848739	23365008	23365172

Expression profiles

Bgee: expression breadth ubiquitous, 265 present calls, max score 97.16.

FANTOM5 (CAGE): breadth broad, TPM avg 4.0478 / max 83.2694, expressed in 781 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142356	3.1983	710
142357	0.4556	320
142358	0.3939	126

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	97.16	gold quality
inferior vagus X ganglion	UBERON:0005363	96.87	gold quality
cervix squamous epithelium	UBERON:0006922	96.72	gold quality
mammalian vulva	UBERON:0000997	95.58	gold quality
embryo	UBERON:0000922	95.18	gold quality
ventricular zone	UBERON:0003053	95.18	gold quality
middle frontal gyrus	UBERON:0002702	95.14	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.12	gold quality
spinal cord	UBERON:0002240	95.08	gold quality
gingival epithelium	UBERON:0001949	94.67	gold quality
skin of abdomen	UBERON:0001416	94.54	gold quality
subthalamic nucleus	UBERON:0001906	94.48	gold quality
gingiva	UBERON:0001828	94.30	gold quality
skin of leg	UBERON:0001511	94.02	gold quality
skin of hip	UBERON:0001554	93.90	gold quality
zone of skin	UBERON:0000014	93.85	gold quality
nerve	UBERON:0001021	93.70	gold quality
tibial nerve	UBERON:0001323	93.70	gold quality
ectocervix	UBERON:0012249	93.64	gold quality
penis	UBERON:0000989	93.62	gold quality
medulla oblongata	UBERON:0001896	93.56	gold quality
endocervix	UBERON:0000458	93.32	gold quality
globus pallidus	UBERON:0001875	93.31	gold quality
lower esophagus mucosa	UBERON:0035834	93.26	gold quality
medial globus pallidus	UBERON:0002477	93.20	gold quality
upper leg skin	UBERON:0004262	93.20	gold quality
lateral globus pallidus	UBERON:0002476	93.12	gold quality
parotid gland	UBERON:0001831	92.90	gold quality
vagina	UBERON:0000996	92.84	gold quality
nipple	UBERON:0002030	92.74	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.83

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

54 targeting EFS, 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-5692A	100.00	74.40	6850
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4262	100.00	73.26	3931
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-LET-7C-3P	99.95	73.42	2862
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-377-5P	99.70	65.28	712
HSA-MIR-6086	99.70	65.38	699
HSA-MIR-4716-3P	99.69	66.73	1022
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4677-3P	99.49	67.91	1246
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-653-5P	99.46	67.35	1300
HSA-MIR-32-3P	99.36	68.20	2517

Literature-anchored findings (GeneRIF, showing 4)

• Analysis of 16 Uveal melanoma showed full methylation of the EFS CpG island in 8 (50%), no methylation in 5(31%)and partial methylation in 3 (19%)tumors. Kaplan-Meier analysis revealed higher risk of metastatic progression for tumors with EFS methylation. (PMID:21871071)
• we suggest that EFS should be considered as a novel tumor suppressor gene in prostate cancer. (PMID:25296736)
• EFS and CASS4 protein function in the context of the larger CAS family group. [Review] (PMID:26119091)
• The combined use of EFS, GPX2, and SPRR1A expression could distinguish favorable from poor clinical outcome among epithelial-like head and neck carcinoma subtypes. (PMID:30652380)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	efs	ENSDARG00000088835
mus_musculus	Efs	ENSMUSG00000022203
rattus_norvegicus	Efs	ENSRNOG00000042029
drosophila_melanogaster	p130CAS	FBGN0035101

Paralogs (3): BCAR1 (ENSG00000050820), CASS4 (ENSG00000087589), NEDD9 (ENSG00000111859)

Protein

Protein identifiers

Embryonal Fyn-associated substrate — O43281 (reviewed: O43281)

Alternative names: Cas scaffolding protein family member 3

All UniProt accessions (1): O43281

UniProt curated annotations — full annotation on UniProt →

Function. Docking protein which plays a central coordinating role for tyrosine-kinase-based signaling related to cell adhesion. May serve as an activator of SRC and a downstream effector. Interacts with the SH3 domain of FYN and with CRK, SRC, and YES.

Tissue specificity. The protein has been detected in lung and placenta.

Post-translational modifications. Phosphorylated on multiple tyrosine residues. Phosphorylated on tyrosines by FYN and SRC.

Domain organisation. Contains a central domain (substrate domain) containing multiple potential SH2-binding sites and a C-terminal domain containing a divergent helix-loop-helix (HLH) motif. The SH2-binding sites putatively bind CRK, NCK and ABL SH2 domains. The SH3-binding sites that bind to the SRC SH3 domain are required for interaction with CRK and are implicated in promotion of serum response element (SRE) activation. The SH3 domain interacts with PTK2/FAK1.

Similarity. Belongs to the CAS family.

Isoforms (3)

UniProt ID	Names	Canonical?
O43281-1	Efs1	yes
O43281-2	Efs2
O43281-3	3

RefSeq proteins (4): NP_001264103, NP_001372536, NP_005855, NP_115835 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR021901	CAS_C	Domain
IPR035747	EFS_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR037362	CAS_fam	Family

Pfam: PF12026, PF14604

UniProt features (18 total): region of interest 5, compositionally biased region 3, sequence variant 3, splice variant 2, short sequence motif 2, chain 1, domain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43281-F1	61.71	0.30

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 (1): 253

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 116 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, JAEGER_METASTASIS_DN, MODULE_45, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, CHANDRAN_METASTASIS_DN, CAGCTG_AP4_Q5, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A5, MODULE_66, BLALOCK_ALZHEIMERS_DISEASE_UP, WONG_ENDMETRIUM_CANCER_DN, SCHLOSSER_SERUM_RESPONSE_DN, MODULE_88, ONGUSAHA_TP53_TARGETS, CCCNNGGGAR_OLF1_01, MODULE_11

GO Biological Process (4): cell adhesion (GO:0007155), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), cell migration (GO:0016477), intracellular signal transduction (GO:0035556)

GO Molecular Function (3): SH3 domain binding (GO:0017124), protein domain specific binding (GO:0019904), protein binding (GO:0005515)

GO Cellular Component (3): cytoplasm (GO:0005737), focal adhesion (GO:0005925), plasma membrane (GO:0005886)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
cellular process	1
enzyme-linked receptor protein signaling pathway	1
cell motility	1
signal transduction	1
protein domain specific binding	1
protein binding	1
binding	1
cellular anatomical structure	1
cell-substrate junction	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1978 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EFS	CSE1L	P55060	769
EFS	CASP3	P42574	725
EFS	BCL2	P10415	723
EFS	CASZ1	Q86V15	651
EFS	CASS4	Q9NQ75	617
EFS	CRK	P46108	565
EFS	TGFBI	Q15582	522
EFS	TMEM63C	Q9P1W3	520
EFS	ACR	P10323	509
EFS	ANXA5	P08758	497
EFS	CASP9	P55211	490
EFS	CSN1S1	P47710	488
EFS	CSH1	P01243	487
EFS	FYN	P06241	474
EFS	BCAR1	P56945	450

IntAct

47 interactions, top by confidence:

A	B	Type	Score
EFS	ABI2	psi-mi:“MI:0915”(physical association)	0.740
ABI2	EFS	psi-mi:“MI:0915”(physical association)	0.740
BLK	EFS	psi-mi:“MI:0915”(physical association)	0.710
EFS	BLK	psi-mi:“MI:0915”(physical association)	0.710
EFS	FYN	psi-mi:“MI:0915”(physical association)	0.670
FYN	EFS	psi-mi:“MI:0915”(physical association)	0.670
EFS	NUP155	psi-mi:“MI:0915”(physical association)	0.560
EFS	SORBS2	psi-mi:“MI:0915”(physical association)	0.560
ZNF417	EFS	psi-mi:“MI:0915”(physical association)	0.560
EFS	OSTF1	psi-mi:“MI:0915”(physical association)	0.560
EFS	TSSK1B	psi-mi:“MI:0915”(physical association)	0.560
TSSK1B	EFS	psi-mi:“MI:0915”(physical association)	0.560
SORBS2	EFS	psi-mi:“MI:0915”(physical association)	0.560
EFS	ZNF417	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (51): EFS (Two-hybrid), EFS (Two-hybrid), EFS (Two-hybrid), EFS (Two-hybrid), EFS (Two-hybrid), OSTF1 (Two-hybrid), TSSK1B (Two-hybrid), ZNF417 (Two-hybrid), EFS (Two-hybrid), TRAPPC6A (Two-hybrid), EFS (Two-hybrid), EFS (Two-hybrid), EFS (Two-hybrid), EFS (Two-hybrid), EFS (Two-hybrid)

ESM2 similar proteins: A5PKL7, D3ZZN9, O15049, O43281, O94989, O95153, P56945, P60669, Q07912, Q13671, Q15772, Q16584, Q2M3G4, Q2M3V2, Q3LUD3, Q3LUD4, Q3UYR4, Q494U1, Q5BJT1, Q5FWH6, Q5SW24, Q5XJV6, Q61140, Q62407, Q63767, Q64355, Q66HA1, Q6PAJ3, Q6ZMQ8, Q6ZS72, Q6ZVH7, Q6ZW31, Q75VX8, Q7TNF8, Q80W87, Q80XI6, Q8BG26, Q8BLS7, Q8TER5, Q8VC98

Diamond homologs: A0A8I3PDQ1, A1CEK6, A1DFN5, A2QW93, A4FU49, A4RF61, A7A261, O13736, O35177, O35179, O35964, O42287, O43281, P29355, P34109, P38753, P43603, P56945, Q08012, Q0CJU8, Q0P5B1, Q0U6X7, Q14511, Q15811, Q16584, Q1E878, Q2GT05, Q4R729, Q4WHP5, Q557J6, Q5BBL4, Q5I1X5, Q61140, Q62419, Q62420, Q63767, Q64355, Q66HA1, Q6BNP6, Q6C2N2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 22 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
Downstream signal transduction	8	160.3×	2e-14
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	5	93.9×	1e-07
RHOU GTPase cycle	5	73.3×	4e-07
FCGR3A-mediated phagocytosis	7	69.0×	5e-10
VEGFA-VEGFR2 Pathway	8	58.6×	6e-11
Regulation of actin dynamics for phagocytic cup formation	5	48.5×	2e-06
RAF/MAP kinase cascade	5	16.1×	1e-04
Signaling by Receptor Tyrosine Kinases	5	13.6×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
ephrin receptor signaling pathway	6	93.8×	1e-08
epidermal growth factor receptor signaling pathway	6	67.6×	6e-08
cell migration	6	16.8×	8e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	87
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

893 predictions. Top by Δscore:

Variant	Effect	Δscore
14:23360136:CTCA:C	donor_loss	1.0000
14:23360137:TCA:T	donor_loss	1.0000
14:23360138:CAC:C	donor_loss	1.0000
14:23360139:ACC:A	donor_loss	1.0000
14:23360279:CAC:C	acceptor_gain	1.0000
14:23359311:GCTCA:G	donor_loss	0.9900
14:23359312:CTCAC:C	donor_loss	0.9900
14:23359313:TCACC:T	donor_loss	0.9900
14:23359314:CACC:C	donor_loss	0.9900
14:23359315:ACCT:A	donor_loss	0.9900
14:23359316:C:CG	donor_loss	0.9900
14:23360139:A:AC	donor_gain	0.9900
14:23360140:C:CC	donor_gain	0.9900
14:23360140:CCT:C	donor_gain	0.9900
14:23360142:T:TA	donor_gain	0.9900
14:23360277:TACAC:T	acceptor_gain	0.9900
14:23360280:ACCT:A	acceptor_loss	0.9900
14:23360283:T:C	acceptor_loss	0.9900
14:23360556:T:TA	donor_gain	0.9900
14:23364993:C:CA	donor_gain	0.9900
14:23365001:GACT:G	donor_loss	0.9900
14:23365002:ACTC:A	donor_loss	0.9900
14:23365003:CT:C	donor_loss	0.9900
14:23365004:TCAC:T	donor_loss	0.9900
14:23365005:CACC:C	donor_loss	0.9900
14:23365007:CCGA:C	donor_gain	0.9900
14:23360139:ACCT:A	donor_gain	0.9800
14:23360140:CCTC:C	donor_gain	0.9800
14:23360282:C:CC	acceptor_gain	0.9800
14:23364999:TGGAC:T	donor_loss	0.9800

AlphaMissense

3526 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:23360775:A:G	F26S	0.997
14:23360774:G:C	F26L	0.996
14:23360774:G:T	F26L	0.996
14:23360776:A:G	F26L	0.996
14:23360714:C:A	W46C	0.995
14:23360714:C:G	W46C	0.995
14:23360666:C:A	R62S	0.993
14:23360666:C:G	R62S	0.993
14:23360716:A:G	W46R	0.993
14:23360716:A:T	W46R	0.993
14:23360804:G:C	N16K	0.993
14:23360804:G:T	N16K	0.993
14:23360679:A:T	V58E	0.992
14:23360686:C:G	G56R	0.992
14:23360667:C:A	R62M	0.991
14:23360704:A:G	S50P	0.991
14:23360757:A:G	L32P	0.991
14:23360707:A:G	C49R	0.990
14:23360676:G:T	P59H	0.988
14:23360686:C:A	G56C	0.988
14:23360705:G:C	C49W	0.988
14:23360685:C:A	G56V	0.987
14:23360775:A:C	F26C	0.987
14:23360781:A:G	L24P	0.987
14:23360667:C:G	R62T	0.984
14:23360823:G:T	A10D	0.984
14:23360700:A:G	L51P	0.983
14:23360668:T:C	R62G	0.981
14:23360766:C:A	G29V	0.981
14:23360785:C:T	E23K	0.980

dbSNP variants (sampled 300 via entrez): RS1000118659 (14:23361148 T>G), RS1000126704 (14:23356000 A>G), RS1000196687 (14:23355999 T>A,C), RS1000306336 (14:23367091 C>G,T), RS1000510609 (14:23361509 T>C), RS1000583279 (14:23357132 T>C), RS1000592372 (14:23366122 G>A,C,T), RS1000693406 (14:23361566 G>A), RS1001594196 (14:23363204 C>A,T), RS1002368169 (14:23357648 G>T), RS1002955802 (14:23363522 C>A,T), RS1002965860 (14:23363301 G>A), RS1003034332 (14:23360136 C>G,T), RS1003300974 (14:23364650 A>G), RS1003471757 (14:23358631 C>A)

Disease associations

OMIM: gene MIM:609906 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects cotreatment, decreases expression, affects expression	9
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
bisphenol A	affects cotreatment, increases expression	1
sodium arsenate	decreases expression, increases abundance	1
propionic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
clothianidin	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
Sunitinib	decreases expression	1
Arbutin	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases methylation	1
Carbamazepine	affects expression	1
Dexamethasone	affects cotreatment, increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Formaldehyde	increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Progesterone	decreases expression, affects cotreatment	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Tunicamycin	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Antirheumatic Agents	increases expression	1
tert-Butylhydroperoxide	increases expression	1

Clinical trials (associated diseases)

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