ETV6

Chr 12AD

ETS variant transcription factor 6

Also known as: TEL, TEL/ABL, THC5

NCBI Gene: 2120 ENSG00000139083 UniProt: P41212 OMIM: 600618

This gene encodes an ETS family transcriptional repressor that binds specific DNA sequences and is required for hematopoiesis and vascular network development. Mutations cause autosomal dominant thrombocytopenia 5, and somatic mutations are associated with acute myeloid leukemia. The gene is highly constrained against loss-of-function variants (pLI 0.97), indicating that such mutations are likely to have significant clinical consequences.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Leukemia, acute myeloid, somaticMIM #601626

Thrombocytopenia 5MIM #616216

UniProtMyeloproliferative disorder chronic with eosinophilia

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · thrombocytopenia 5 · AD · ClinGen 2020

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

294

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.32

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

📖

GeneReview available — ETV6

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.32LOEUF

pLI 0.974

Z-score 4.02

OE 0.12 (0.06–0.32)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.78Z-score

OE missense 0.70 (0.62–0.79)

196 obs / 279.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.12 (0.06–0.32)

0≤0.351.4

Missense OE?0.70 (0.62–0.79)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 3 / 24.4Missense obs/exp: 196 / 279.9Syn Z: -1.32

Background carrier burden — how many people carry a rare variant somewhere in ETV6?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

510 rare PASS variants

Rare truncating (LoF)

1 in 1,600

38 rare PASS variants

Rare synonymous (reference)

1 in 94

269 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ETV6. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 170	1 in 1,800
South Asian	~43k	1 in 96	1 in 3,000
Remaining (unassigned)	~30k	1 in 100	1 in 2,100
European (Finnish)	~27k	1 in 330	none seen
Admixed American	~22k	1 in 160	1 in 570
African / African American	~21k	1 in 140	≈ 1 in 4,800
East Asian	~20k	1 in 93	1 in 1,200
Ashkenazi Jewish	~13k	1 in 1,900	≈ 1 in 4,200
Middle Eastern	~2,884	1 in 140	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 8 coding exons well covered in gnomAD exomes and genomes.? see exons ↓