ERF

protein-coding

ETS2 repressor factor, the group of ETS transcription factor family

Gene summary

ETS2 is a transcription factor and protooncogene involved in development, apoptosis, and the regulation of telomerase. The protein encoded by this gene binds to the ETS2 promoter and is a strong repressor of ETS2 transcription. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

MANE transcript

NM_006494.4

Inheritance

ClinVar variants

P:66U:175B:76

Top phenotype

Chitayat syndrome

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr19:42,247,569-42,255,128

External References & Databases

Ensembl (ENSG00000105722)

Transcript & Mutation Effects

hg38 • Region Span ~7.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

craniosynostosis 4DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010929

Submitter: G2P

craniosynostosis 4MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0010929

Submitter: Ambry Genetics

Chitayat syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014956

Submitter: G2P

Noonan syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: PanelApp Australia

Chitayat syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014956

Submitter: Ambry Genetics

craniosynostosis 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010929

Submitter: Genomics England PanelApp

craniosynostosis 4DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010929

Submitter: ClinGen

ERF was first reported in relation to autosomal dominant ERF-related craniosynostosis in 2013 (Twigg et al., PMID: 23354439). The phenotypic features of "ERF-related craniosynostosis" often include sagittal or multiple-suture synostosis, Chiari malformation, and language delay. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the phenotypic and genotypic variability between ERF-related craniosynostosis and Chitayat syndrome. Therefore, the two disease entities have been split. The split curation for autosomal dominant Chitayat syndrome will be curated separately. Ten variants (missense, nonsense, splice, frameshift) that have been reported in 12 probands in 3 publications (PMIDs: 23354439, 26097063, 31754721) are included in this curation. 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 heterozygous loss of function (haploinsufficiency) (PMID: 23354439). This gene-disease association is supported by an expression study and a conditional mouse model (PMID: 23354439). In summary, ERF is definitively associated autosomal dominant ERF-related craniosynostosis. 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 Craniofacial Malformations GCEP on the meeting date 5/20/2021.

craniosynostosis 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010929

Submitter: Labcorp Genetics (formerly Invitae)

Chitayat syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014956

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Chitayat syndromeAD

Manifestation: Craniofacial; Musculoskeletal; Neurologic; Pulmonary

Intervention: Pulmonary

Rationale: Among other features, Chitayat syndrome can include neonatal respiratory distress requiring ventilatory support, and awareness may allow early recognition and management

Refs: 8418638; 23354439; 26097063; 27738187

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ERF variants in ClinVar

20 Conditions Cataloged

not providedTotal: 125

TWIST1-related craniosynostosisTotal: 103

Inborn genetic diseasesTotal: 90

Lambdoidal craniosynostosisTotal: 32

not specifiedTotal: 25

ERF-related disorderTotal: 24

Chitayat syndromeTotal: 15

Craniosynostosis 4Total: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006494.4. 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	52 clinvar	5 clinvar	60
missense	1 clinvar	8 clinvar	162 clinvar	18 clinvar	1 clinvar	190
nonsense	8 clinvar	10 clinvar	1 clinvar			19
start loss	2 clinvar	1 clinvar				3
frameshift	13 clinvar	18 clinvar	6 clinvar			37
splice donor/acceptor (+/-2bp)	3 clinvar	2 clinvar	3 clinvar			8
Total	27	39	175	70	6	317

Highest pathogenic variant AF is 0.0000031243517

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006494.4	RefSeq	NP_006485.2	4	MANE Select
ENST00000222329.9	Ensembl	ENSP00000222329.3	4	MANE Select
NM_001301035.2	RefSeq	NP_001287964.1	3	Standard
NM_001308402.2	RefSeq	NP_001295331.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Oncogene Induced Senescence
Cellular Senescence
Cellular responses to stress
Cellular responses to external stimuli

Biological Process

negative regulation of transcription by RNA polymerase II
mitotic cell cycle
regulation of transcription by RNA polymerase II
cell differentiation

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription repressor activity, RNA polymerase II-specific
transcription corepressor activity
sequence-specific DNA binding

Cellular Component

nucleus
nucleoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000222329
Coding exons: 4
Length: 7586
Individuals with no LoFs: 125719
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125723
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.25	238	358	0.665	0.0000242	3427
Missense (PolyPhen)		49	110.47	0.44354		1066
Synonymous	-1.84	199	169	1.18	0.0000120	1236
Loss of Function	3.73	1	18.2	0.0551	0.00000101	196

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000028	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Potent transcriptional repressor that binds to the H1 element of the Ets2 promoter. May regulate other genes involved in cellular proliferation. Required for extraembryonic ectoderm differentiation, ectoplacental cone cavity closure, and chorioallantoic attachment (By similarity). May be important for regulating trophoblast stem cell differentiation (By similarity). {ECO:0000250}.;
Disease: DISEASE: Craniosynostosis 4 (CRS4) [MIM:600775]: A primary abnormality of skull growth involving premature fusion of one or more cranial sutures. The growth velocity of the skull often cannot match that of the developing brain resulting in an abnormal head shape and, in some cases, increased intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability. {ECO:0000269|PubMed:23354439}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Chitayat syndrome (CHYTS) [MIM:617180]: An autosomal dominant syndrome characterized by hyperphalangism, partial syndactyly, bilateral accessory phalanx resulting in shortened index fingers, hallux valgus, brachydactyly, facial anomalies, diffuse bronchomalacia, and respiratory distress at birth and in infancy. {ECO:0000269|PubMed:27738187}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.139

Intolerance Scores

LoFtool: 0.0200
RVIS EVS: -0.42
RVIS percentile EVS: 25.56

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.994

Gene Damage Prediction

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