LEF1

protein-coding

lymphoid enhancer binding factor 1, the group of TCF/LEF transcription factor family|Wnt enhanceosome complex

Gene summary

This gene encodes a transcription factor belonging to a family of proteins that share homology with the high mobility group protein-1. The protein encoded by this gene can bind to a functionally important site in the T-cell receptor-alpha enhancer, thereby conferring maximal enhancer activity. This transcription factor is involved in the Wnt signaling pathway, and it may function in hair cell differentiation and follicle morphogenesis. Mutations in this gene have been found in somatic sebaceous tumors. This gene has also been linked to other cancers, including androgen-independent prostate cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

MANE transcript

NM_016269.5

Inheritance

AD, AR

ClinVar variants

P:4U:59B:4

Top phenotype

ectodermal dysplasia 17 with or without limb malformations

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr4:108,047,545-108,168,956

External References & Databases

Ensembl (ENSG00000138795)

Transcript & Mutation Effects

hg38 • Region Span ~121.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ectodermal dysplasia 17 with or without limb malformationsSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0979228

Submitter: PanelApp Australia

ectodermal dysplasia 17 with or without limb malformationsLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0979228

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LEF1 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 45

not providedTotal: 11

Ectodermal dysplasia 17 with or without limb malformationsTotal: 6

EctrodactylyTotal: 2

LEF1-related disorderTotal: 1

Radial ray deficiencyTotal: 1

Ectrodactyly and ectodermal dysplasia without cleft lip/palateTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016269.5. 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			2 clinvar	2 clinvar	1 clinvar	5
missense			49 clinvar	1 clinvar		50
nonsense			2 clinvar			2
start loss						0
frameshift	2 clinvar	2 clinvar				4
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	2	2	59	3	1	67

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016269.5	RefSeq	NP_057353.1	11	MANE Select
ENST00000265165.6	Ensembl	ENSP00000265165.1	11	MANE Select
NM_001130713.3	RefSeq	NP_001124185.1	10	Standard
NM_001130714.3	RefSeq	NP_001124186.1	10	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
lef1	Danio rerio	Structure: melanocyte Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

lef1

Danio rerio

Structure: melanocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Gastric cancer - Homo sapiens (human)
Adherens junction - Homo sapiens (human)
Cushing,s syndrome - Homo sapiens (human)
Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Homo sapiens (human)
Acute myeloid leukemia - Homo sapiens (human)

Biological Process

negative regulation of transcription by RNA polymerase II
branching involved in blood vessel morphogenesis
osteoblast differentiation
somitogenesis
epithelial to mesenchymal transition

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
DNA binding

Cellular Component

nucleus
nucleoplasm
transcription factor complex
cytoplasm
protein-DNA complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000265165
Coding exons: 11
Length: 121412
Individuals with no LoFs: 125742
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125747
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.57	167	235	0.711	0.0000119	2619
Missense (PolyPhen)		71	120.24	0.59047		1386
Synonymous	0.282	86	89.4	0.962	0.00000521	750
Loss of Function	4.19	1	22.4	0.0446	9.49e-7	277

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	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Participates in the Wnt signaling pathway. Activates transcription of target genes in the presence of CTNNB1 and EP300. May play a role in hair cell differentiation and follicle morphogenesis. TLE1, TLE2, TLE3 and TLE4 repress transactivation mediated by LEF1 and CTNNB1. Regulates T-cell receptor alpha enhancer function. Binds DNA in a sequence-specific manner. PIAG antagonizes both Wnt-dependent and Wnt-independent activation by LEF1 (By similarity). Isoform 3 lacks the CTNNB1 interaction domain and may be an antagonist for Wnt signaling. Isoform 5 transcriptionally activates the fibronectin promoter, binds to and represses transcription from the E-cadherin promoter in a CTNNB1- independent manner, and is involved in reducing cellular aggregation and increasing cell migration of pancreatic cancer cells. Isoform 1 transcriptionally activates MYC and CCND1 expression and enhances proliferation of pancreatic tumor cells. {ECO:0000250, ECO:0000269|PubMed:11266540, ECO:0000269|PubMed:19653274, ECO:0000269|PubMed:2010090}.;

Recessive Scores

pRec: 0.832

Intolerance Scores

LoFtool: 0.0162
RVIS EVS: 0.2
RVIS percentile EVS: 67.19

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.988

Gene Damage Prediction

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