GeneBe

ETV6

protein-coding

ETS variant transcription factor 6, the group of ETS transcription factor family

Gene summary

This gene encodes an ETS family transcription factor. The product of this gene contains two functional domains: a N-terminal pointed (PNT) domain that is involved in protein-protein interactions with itself and other proteins, and a C-terminal DNA-binding domain. Gene knockout studies in mice suggest that it is required for hematopoiesis and maintenance of the developing vascular network. This gene is known to be involved in a large number of chromosomal rearrangements associated with leukemia and congenital fibrosarcoma. [provided by RefSeq, Sep 2008]

MANE transcript

NM_001987.5

Inheritance

AD

ClinVar variants

P:72U:500B:357

Top phenotype

Thrombocytopenia 5

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr12:11,649,674-11,895,377

External References & Databases

Ensembl (ENSG00000139083)NCBI Gene (2120)OMIM (600618)HGNC:3495GenCCUniProt (P41212)AlphaFoldClinVar (ETV6)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~245.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

thrombocytopenia 5DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014536

Submitter: Ambry Genetics

acute myeloid leukemiaLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0018874

Submitter: Ambry Genetics

thrombocytopenia 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014536

Submitter: Labcorp Genetics (formerly Invitae)

acute myeloid leukemiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0018874

Submitter: Genomics England PanelApp

thrombocytopenia 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014536

Submitter: PanelApp Australia

thrombocytopenia 5DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014536

Submitter: ClinGen

ETV6 was first reported in relation to autosomal dominant thrombocytopenia 5 in 2015 (Zhang et al., 2015; PMID: 25581430). At least 16 unique variants (largely missense, but also nonsense and frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 20 probands in 7 publications (PMIDs: 25581430, 25807284, 26102509, 27365488, 27663637, 26522332, 29034503). Variants in this gene segregated with disease in 51 additional family members. This gene-disease relationship is supported by the biochemical function of ETV6 as a master hematopoietic transcription factor (PMID: 10514502), it’s functional alteration in both patient (PMID: 27365488, 27663637) and non-patient cells (PMIDs: 25581430, 25807284), as well as a knockdown Zebrafish model (PMID: 25281506) and a conditional knockout mouse model (PMID: 15371326). In summary, ETV6 is definitively associated with autosomal dominant thrombocytopenia 5. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Clinical Genomic Database (CGD)

Thrombocytopenia 5AD

Manifestation: Hematologic; Oncologic

Intervention: Hematologic; Oncologic

Rationale: Individuals have bleeding tendency, and awareness may allow preventive measures and early management of bleeding episodes; Individuals are at risk of hematologic malignancy (other other cancer types have also been reported), and awareness may allow early diagnosis and management; HSCT has been described

Refs: 25581430; 25807284Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ETV6 variants in ClinVar

16 Conditions Cataloged
Inborn genetic diseasesTotal: 828
not providedTotal: 390
not specifiedTotal: 74
ETV6-related disorderTotal: 50
Thrombocytopenia 5Total: 43
ETV6-related disordersTotal: 16
ThrombocytopeniaTotal: 13
Acute myeloid leukemiaTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001987.5. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
280
clinvar
 282
missense
1
clinvar
12
clinvar
477
clinvar
75
clinvar
1
clinvar
 566
nonsense
9
clinvar
3
clinvar
6
clinvar
 18
start loss
2
clinvar
 2
frameshift
20
clinvar
13
clinvar
7
clinvar
 40
splice donor/acceptor (+/-2bp)
3
clinvar
11
clinvar
6
clinvar
1
clinvar
 21
Total33395003561929

Highest pathogenic variant AF is 0.000006568921

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 30 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001987.5RefSeqNP_001978.18MANE Select
ENST00000396373.9EnsemblENSP00000379658.38MANE Select
NM_001413913.1RefSeqNP_001400842.18Standard
NM_001413914.1RefSeqNP_001400843.18Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
etv6Danio rerio

Structure: whole organism

Quality: has extra parts of type

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Transcriptional misregulation in cancer - Homo sapiens (human)
  • Hematopoietic Stem Cell Gene Regulation by GABP alpha-beta Complex
  • Exercise-induced Circadian Regulation
  • FGF

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • regulation of transcription by RNA polymerase II
  • vitellogenesis
  • neurogenesis
  • cell differentiation

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 repressor activity, RNA polymerase II-specific
  • DNA-binding transcription activator activity, RNA polymerase II-specific

Cellular Component

  • nucleus
  • nucleolus
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000396373
Coding exons
8
Length
245549
Individuals with no LoFs
125739
Homozygous LoFs
0
Heterozygous LoFs
7
Defined
125746
p
0.0000278
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.781962800.7000.00001762973
Missense (PolyPhen)2580.7630.30955897
Synonymous-1.321281101.160.00000698882
Loss of Function4.02324.40.1230.00000162226

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000350.000035rare
South Asian0.0000330.000033rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Transcriptional repressor; binds to the DNA sequence 5'- CCGGAAGT-3'. Plays a role in hematopoiesis and malignant transformation. {ECO:0000269|PubMed:25581430}.;
Disease
DISEASE: Note=A chromosomal aberration involving ETV6 is found in a form of chronic myelomonocytic leukemia (CMML). Translocation t(5;12)(q33;p13) with PDGFRB. It is characterized by abnormal clonal myeloid proliferation and by progression to acute myelogenous leukemia (AML). {ECO:0000269|PubMed:8168137}.; DISEASE: Note=Chromosomal aberrations involving ETV6 are found in acute myeloid leukemia (AML). Translocation t(12;22)(p13;q11) with MN1 (PubMed:7731705). Translocation t(4;12)(q12;p13) with CHIC2 (PubMed:10477709). {ECO:0000269|PubMed:10477709, ECO:0000269|PubMed:7731705}.; DISEASE: Note=Chromosomal aberrations involving ETV6 are found in childhood acute lymphoblastic leukemia (ALL). Translocations t(12;21)(p12;q22) and t(12;21)(p13;q22) with RUNX1/AML1. {ECO:0000269|PubMed:7761424}.; DISEASE: Note=A chromosomal aberration involving ETV6 is found in a form of pre-B acute lymphoid leukemia. Translocation t(9;12)(p24;p13) with JAK2. {ECO:0000269|PubMed:9326218}.; DISEASE: Note=A chromosomal aberration involving ETV6 and JAK2 is found in an atypical chronic myelogenous leukemia. Translocation t(9;15;12)(p24;q15;p13). {ECO:0000269|PubMed:9326218}.; DISEASE: Note=A chromosomal aberration involving ETV6 is found in myelodysplastic syndrome (MDS) with basophilia. Translocation t(5;12)(q31;p13) with ACSL6. {ECO:0000269|PubMed:10502316}.; DISEASE: Note=A chromosomal aberration involving ETV6 is found in acute eosinophilic leukemia (AEL). Translocation t(5;12)(q31;p13) with ACSL6. {ECO:0000269|PubMed:10502316}.; DISEASE: Note=A chromosomal aberration involving ETV6 is found in myelodysplastic syndrome (MDS). Translocation t(1;12)(p36.1;p13) with MDS2. {ECO:0000269|PubMed:12203785}.; DISEASE: Note=A chromosomal aberration involving ETV6 is found in acute lymphoblastic leukemia. Translocation t(9;12)(p13;p13) with PAX5. {ECO:0000269|PubMed:17344859}.; DISEASE: Myeloproliferative disorder chronic with eosinophilia (MPE) [MIM:131440]: A hematologic disorder characterized by malignant eosinophils proliferation. {ECO:0000269|PubMed:12181402}. Note=The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving ETV6 is found in many instances of myeloproliferative disorder chronic with eosinophilia. Translocation t(5;12) with PDGFRB on chromosome 5 creating an ETV6-PDGFRB fusion protein. {ECO:0000269|PubMed:12181402}.; DISEASE: Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. {ECO:0000269|PubMed:15806161}. Note=The gene represented in this entry is involved in disease pathogenesis.; DISEASE: Thrombocytopenia 5 (THC5) [MIM:616216]: Thrombocytopenia is defined by a decrease in the number of platelets in circulating blood, resulting in the potential for increased bleeding and decreased ability for clotting. THC5 is an autosomal dominant disorder, associated with an increased susceptibility to the development of hematologic and solid malignancies. {ECO:0000269|PubMed:25581430}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.514

Intolerance Scores

LoFtool
0.177
RVIS EVS
-0.62
RVIS percentile EVS
17.16

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
N
Essential (gene trap)
K
Indispensability pred.
E
Indispensability score
0.803

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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