EBF3

protein-coding

EBF transcription factor 3, the group of MicroRNA protein coding host genes|IPT domain containing|Early B-cell factors

Gene summary

This gene encodes a member of the early B-cell factor (EBF) family of DNA binding transcription factors. EBF proteins are involved in B-cell differentiation, bone development and neurogenesis, and may also function as tumor suppressors. The encoded protein inhibits cell survival through the regulation of genes involved in cell cycle arrest and apoptosis, and aberrant methylation or deletion of this gene may play a role in multiple malignancies including glioblastoma multiforme and gastric carcinoma. [provided by RefSeq, Sep 2011]

MANE transcript

NM_001375380.1

Inheritance

ClinVar variants

P:120U:162B:59

Top phenotype

Hypotonia, ataxia, and delayed development syndrome (HADDS)

gnomAD constraint

pLI —, LoF o/e 0.03

Max pathogenic AF

—

Genomic locus

chr10:129,835,233-129,973,053

External References & Databases

Ensembl (ENSG00000108001)

Transcript & Mutation Effects

hg38 • Region Span ~137.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypotonia, ataxia, and delayed development syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015021

Submitter: Labcorp Genetics (formerly Invitae)

hypotonia, ataxia, and delayed development syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015021

Submitter: G2P

hypotonia, ataxia, and delayed development syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015021

Submitter: PanelApp Australia

hypotonia, ataxia, and delayed development syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015021

Submitter: ClinGen

*EBF3* was first reported in relation to autosomal dominant hypotonia, ataxia, and delayed development syndrome (HADDS) in 2017 (Sleven et al., PMID: 28017370; Chao et al., PMID: 28017372; Harms et al., PMID: 28017373). HADDS is a neurodevelopmental syndrome characterized by congenital hypotonia, delayed psychomotor development, intellectual disability with speech delay, variable dysmorphic facial features, and ataxia, often related to cerebellar hypoplasia. Less frequently, urogenital abnormalities, short stature, microcephaly, etc. may be observed. Ten variants (missense, nonsense, frameshift, canonical splice site) that have been reported in 10 probands in 5 publications (PMIDs: 28017370, 28017372, 28017373, 34050706, 35340043) are included in this curation. Inheritance of variants is primarily *de novo*. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be LOF, with some publications also indicating a dominant-negative mechanism (PMIDs: 28017370, 28017372, 28017373, 34050706). This gene-disease relationship is also supported by experimental evidence. Variants tested demonstrated functional alterations leading to greatly reduced activity as demonstrated by a luciferase reporter assay. The respective protein variants were mislocalized to the cytoplasm as demonstrated by *in situ* subcellular fractionation (PMID: 28017373). In summary, there is definitive evidence to support the relationship between *EBF3* and autosomal dominant hypotonia, ataxia, and delayed development syndrome (HADDS). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 16, 2023 (SOP Version 9).

Clinical Genomic Database (CGD)

Hypotonia, ataxia, and delayed development syndrome (HADDS)AD

Manifestation: Craniofacial; Genitourinary; Neurologic

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: 28017370; 28017372; 28017373

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EBF3 variants in ClinVar

29 Conditions Cataloged

not providedTotal: 173

Hypotonia, ataxia, and delayed development syndromeTotal: 119

Inborn genetic diseasesTotal: 71

not specifiedTotal: 47

EBF3-related disorderTotal: 39

Intellectual disabilityTotal: 8

See casesTotal: 4

Autism spectrum disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001375380.1. 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			7 clinvar	41 clinvar	1 clinvar	49
missense	13 clinvar	41 clinvar	141 clinvar	17 clinvar		212
nonsense	14 clinvar	5 clinvar	1 clinvar			20
start loss						0
frameshift	17 clinvar	13 clinvar	7 clinvar			37
splice donor/acceptor (+/-2bp)	10 clinvar	7 clinvar	6 clinvar			23
Total	54	66	162	58	1	341

Highest pathogenic variant AF is 0.000007868192

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001375380.1	RefSeq	NP_001362309.1	17	MANE Select
ENST00000440978.2	Ensembl	ENSP00000387543.2	17	MANE Select
NM_001005463.3	RefSeq	NP_001005463.1	16	Standard
NM_001375379.1	RefSeq	NP_001362308.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Differentiation of white and brown adipocyte

Biological Process

multicellular organism development
positive regulation of transcription, DNA-templated
positive regulation of transcription by RNA polymerase II

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
metal ion binding
protein dimerization activity

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000368648
Coding exons: 16
Length: 128559
Individuals with no LoFs: 125543
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125544
p: 0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.61	163	354	0.460	0.0000210	3612
Missense (PolyPhen)		38	96.714	0.39291		950
Synonymous	0.500	146	154	0.949	0.0000111	1061
Loss of Function	5.05	1	31.7	0.0316	0.00000166	342

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)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcriptional activator (PubMed:28017373, PubMed:28017372, PubMed:28017370). Recognizes variations of the palindromic sequence 5'-ATTCCCNNGGGAATT-3' (By similarity). {ECO:0000250|UniProtKB:Q07802, ECO:0000269|PubMed:28017370, ECO:0000269|PubMed:28017372, ECO:0000269|PubMed:28017373}.;

Recessive Scores

pRec: 0.108

Intolerance Scores

LoFtool: 0.0389
RVIS EVS: -0.65
RVIS percentile EVS: 16.44

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.996

Gene Damage Prediction

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