Thrombocytopenia 5

Summary

Thrombocytopenia 5 (MONDO:0014536) is a disease caused by ETV6 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: ETV6 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 43

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thrombocytopenia 5
Mondo ID	MONDO:0014536
OMIM	616216
NCIT	C203436
UMLS	C4015537
MedGen	863974
GARD	0025000
Is cancer (heuristic)	no

Also known as: ETV6 thrombocytopenia · THC5 · thrombocytopenia 5 · thrombocytopenia caused by mutation in ETV6 · thrombocytopenia type 5

Data availability: 43 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › hereditary thrombocytopenia and hematologic cancer predisposition syndrome › thrombocytopenia 5

Related subtypes (1): hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

43 retrieved; paginated sample, class counts are floors:

21 uncertain significance, 6 pathogenic, 5 conflicting classifications of pathogenicity, 5 pathogenic/likely pathogenic, 5 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3390939	NM_006580.4(CLDN16):c.152T>G (p.Val51Gly)	CLDN16	Pathogenic	criteria provided, single submitter
1175817	NM_001987.5(ETV6):c.1196G>A (p.Arg399His)	ETV6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333000	Single allele	ETV6	Pathogenic	criteria provided, single submitter
162220	NM_001987.5(ETV6):c.1195C>T (p.Arg399Cys)	ETV6	Pathogenic	criteria provided, multiple submitters, no conflicts
162221	NM_001987.5(ETV6):c.1106G>A (p.Arg369Gln)	ETV6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162222	NM_001987.5(ETV6):c.641C>T (p.Pro214Leu)	ETV6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3061446	NM_001987.5(ETV6):c.921_922del (p.His308fs)	ETV6	Pathogenic	criteria provided, single submitter
3064526	NM_001987.5(ETV6):c.1254G>T (p.Arg418Ser)	ETV6	Pathogenic	criteria provided, single submitter
3773668	NM_001987.5(ETV6):c.775dup (p.Arg259fs)	ETV6	Pathogenic	criteria provided, single submitter
435100	NM_001987.5(ETV6):c.614del (p.Leu205fs)	ETV6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
626971	NM_001987.5(ETV6):c.1105C>T (p.Arg369Trp)	ETV6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1703825	NM_001987.5(ETV6):c.968C>G (p.Ser323Cys)	ETV6	Likely pathogenic	criteria provided, single submitter
2572125	NM_001987.5(ETV6):c.1254-2A>C	ETV6	Likely pathogenic	criteria provided, single submitter
2628373	NM_001987.5(ETV6):c.133del (p.Glu45fs)	ETV6	Likely pathogenic	criteria provided, single submitter
3390940	NM_001987.5(ETV6):c.1235G>T (p.Gly412Val)	ETV6	Likely pathogenic	criteria provided, single submitter
4528370	NM_001987.5(ETV6):c.1078del (p.Trp360fs)	ETV6	Likely pathogenic	criteria provided, single submitter
1033878	NM_001987.5(ETV6):c.380G>A (p.Arg127Gln)	ETV6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1698990	NM_001987.5(ETV6):c.116G>A (p.Arg39Gln)	ETV6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2441305	NM_001987.5(ETV6):c.439A>T (p.Ile147Leu)	ETV6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
451459	NM_001987.5(ETV6):c.605G>A (p.Arg202Gln)	ETV6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
435099	NM_001987.5(ETV6):c.1152+5A>G	LOC126861452	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030502	NM_001987.5(ETV6):c.406C>G (p.Pro136Ala)	ETV6	Uncertain significance	criteria provided, single submitter
1172743	NM_001987.5(ETV6):c.1113_1120delinsCCCCCCAC (p.Asp372_Asn374delinsProProHis)	ETV6	Uncertain significance	criteria provided, single submitter
1677253	NM_001987.5(ETV6):c.1034T>G (p.Val345Gly)	ETV6	Uncertain significance	criteria provided, single submitter
1684380	NM_001987.5(ETV6):c.1085A>G (p.Asp362Gly)	ETV6	Uncertain significance	no assertion criteria provided
1699041	NM_001987.5(ETV6):c.1152+6del	ETV6	Uncertain significance	criteria provided, single submitter
1703824	NM_001987.5(ETV6):c.1076G>T (p.Arg359Leu)	ETV6	Uncertain significance	criteria provided, single submitter
1800530	NM_001987.5(ETV6):c.985G>A (p.Ala329Thr)	ETV6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1810175	NM_001987.5(ETV6):c.145C>T (p.Arg49Cys)	ETV6	Uncertain significance	criteria provided, multiple submitters, no conflicts
190309	NM_001987.5(ETV6):c.1252A>G (p.Arg418Gly)	ETV6	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ETV6	Definitive	Autosomal dominant	thrombocytopenia 5	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ETV6	Orphanet:146	Differentiated thyroid carcinoma
ETV6	Orphanet:168629	Autosomal thrombocytopenia with normal platelets
ETV6	Orphanet:2030	Fibrosarcoma
ETV6	Orphanet:2665	Congenital mesoblastic nephroma
ETV6	Orphanet:314950	Primary hypereosinophilic syndrome
ETV6	Orphanet:585929	B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1)
ETV6	Orphanet:98823	Chronic myelomonocytic leukemia
CLDN16	Orphanet:31043	Primary hypomagnesemia with hypercalciuria and nephrocalcinosis without severe ocular involvement

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ETV6	HGNC:3495	ENSG00000139083	P41212	Transcription factor ETV6	gencc,clinvar
CLDN16	HGNC:2037	ENSG00000113946	Q9Y5I7	Claudin-16	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ETV6	Transcription factor ETV6	Transcriptional repressor; binds to the DNA sequence 5’-CCGGAAGT-3'.
CLDN16	Claudin-16	Forms paracellular channels: coassembles with CLDN19 into tight junction strands with cation-selective channels through the strands, conveying epithelial permeability in a process known as paracellular tight junction permeability.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ETV6	Other/Unknown	no		Ets_dom, Pointed_dom, SAM/pointed_sf
CLDN16	Other/Unknown	no		Claudin16, PMP22/EMP/MP20/Claudin, Claudin

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mammary duct	1
mucosa of paranasal sinus	1
parotid gland	1
adult mammalian kidney	1
male germ line stem cell (sensu Vertebrata) in testis	1
olfactory segment of nasal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ETV6	252	ubiquitous	marker	mucosa of paranasal sinus, parotid gland, mammary duct
CLDN16	127	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, olfactory segment of nasal mucosa, adult mammalian kidney

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ETV6	2,225
CLDN16	637

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ETV6	P41212	44

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLDN16	Q9Y5I7	76.74

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by membrane-tethered fusions of PDGFRA or PDGFRB	1	1142.0×	0.003	ETV6
Signaling by FLT3 fusion proteins	1	285.5×	0.005	ETV6
Tight junction interactions	1	184.2×	0.005	CLDN16

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intercellular transport	1	8426.0×	0.002	CLDN16
vitellogenesis	1	1685.2×	0.003	ETV6
paracellular transport	1	1203.7×	0.003	CLDN16
metal ion transport	1	936.2×	0.003	CLDN16
renal absorption	1	842.6×	0.003	CLDN16
mesenchymal cell apoptotic process	1	766.0×	0.003	ETV6
intracellular monoatomic cation homeostasis	1	561.7×	0.004	CLDN16
calcium-independent cell-cell adhesion	1	401.2×	0.005	CLDN16
hematopoietic stem cell proliferation	1	324.1×	0.005	ETV6
bicellular tight junction assembly	1	165.2×	0.009	CLDN16
neurogenesis	1	104.0×	0.013	ETV6
cell adhesion	1	18.7×	0.066	CLDN16
cell differentiation	1	14.6×	0.078	ETV6
negative regulation of transcription by RNA polymerase II	1	8.9×	0.118	ETV6
regulation of transcription by RNA polymerase II	1	5.8×	0.164	ETV6

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ETV6	CERITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ETV6	4	4
CLDN16	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CERITINIB	4	ETV6
GILTERITINIB	4	ETV6
ERDAFITINIB	4	ETV6
LY-2874455	1	ETV6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ETV6	11	Binding:11

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

4 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
CERITINIB	4	ETV6
GILTERITINIB	4	ETV6
ERDAFITINIB	4	ETV6
LY-2874455	1	ETV6

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ETV6
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CLDN16

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CLDN16	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.