TPM4

Summary

TPM4 (tropomyosin 4, HGNC:12013) is a protein-coding gene on chromosome 19p13.12-p13.11, encoding Tropomyosin alpha-4 chain (P67936). Binds to actin filaments in muscle and non-muscle cells. It is a selective cancer dependency (DepMap: 19.5% of cell lines).

This gene encodes a member of the tropomyosin family of actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells. Tropomyosins are dimers of coiled-coil proteins that polymerize end-to-end along the major groove in most actin filaments. They provide stability to the filaments and regulate access of other actin-binding proteins. In muscle cells, they regulate muscle contraction by controlling the binding of myosin heads to the actin filament. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 7171 — RefSeq curated summary.

At a glance

• Gene–disease (curated): bleeding disorder, platelet-type, 25 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 21
• Clinical variants (ClinVar): 58 total — 3 pathogenic
• Phenotypes (HPO): 17
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 19.5% of screened cell lines
• MANE Select transcript: NM_003290

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12013
Approved symbol	TPM4
Name	tropomyosin 4
Location	19p13.12-p13.11
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000167460
Ensembl biotype	protein_coding
OMIM	600317
Entrez	7171

Gene structure

Transcript identifiers

Ensembl transcripts: 41 — 14 protein_coding, 10 nonsense_mediated_decay, 10 retained_intron, 7 protein_coding_CDS_not_defined

ENST00000300933, ENST00000344824, ENST00000586193, ENST00000586499, ENST00000586833, ENST00000587201, ENST00000588032, ENST00000588410, ENST00000588483, ENST00000589897, ENST00000590180, ENST00000591226, ENST00000591645, ENST00000592138, ENST00000642221, ENST00000642789, ENST00000643494, ENST00000643579, ENST00000645471, ENST00000646575, ENST00000646974, ENST00000647037, ENST00000647464, ENST00000653961, ENST00000653979, ENST00000654417, ENST00000655004, ENST00000657915, ENST00000658224, ENST00000658489, ENST00000659595, ENST00000663894, ENST00000664983, ENST00000668959, ENST00000670382, ENST00000891514, ENST00000923415, ENST00000962761, ENST00000962762, ENST00000962763, ENST00000962764

RefSeq mRNA: 5 — MANE Select: NM_003290 NM_001145160, NM_001367836, NM_001367837, NM_001367838, NM_003290

CCDS: CCDS12338, CCDS46007, CCDS92548, CCDS92549

Canonical transcript exons

ENST00000643579 — 8 exons

Exon	Start	End
ENSE00001113264	16088027	16088097
ENSE00001113265	16089045	16089120
ENSE00003510432	16081913	16082046
ENSE00003545329	16086423	16086540
ENSE00003553039	16093684	16093753
ENSE00003820226	16101264	16103002
ENSE00003820439	16076495	16076697
ENSE00003866274	16093536	16093598

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 99.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 302.8565 / max 6736.5779, expressed in 1823 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
174369	212.9291	1813
174362	67.9608	1226
174368	8.4994	1666
174365	8.2798	1713
174364	1.6972	837
174370	1.0733	637
174366	0.8967	572
174371	0.5488	164
174363	0.4569	242
174367	0.3697	183

Top tissues by expression

291 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	99.92	gold quality
stromal cell of endometrium	CL:0002255	99.69	gold quality
right coronary artery	UBERON:0001625	99.55	gold quality
ascending aorta	UBERON:0001496	99.48	gold quality
thoracic aorta	UBERON:0001515	99.48	gold quality
gall bladder	UBERON:0002110	99.48	gold quality
body of uterus	UBERON:0009853	99.44	gold quality
left uterine tube	UBERON:0001303	99.42	gold quality
smooth muscle tissue	UBERON:0001135	99.41	gold quality
aorta	UBERON:0000947	99.40	gold quality
descending thoracic aorta	UBERON:0002345	99.40	gold quality
popliteal artery	UBERON:0002250	99.39	gold quality
tibial artery	UBERON:0007610	99.39	gold quality
left coronary artery	UBERON:0001626	99.38	gold quality
tendon	UBERON:0000043	99.37	gold quality
ectocervix	UBERON:0012249	99.36	gold quality
right lung	UBERON:0002167	99.31	gold quality
coronary artery	UBERON:0001621	99.29	gold quality
upper lobe of left lung	UBERON:0008952	99.29	gold quality
endocervix	UBERON:0000458	99.27	gold quality
right ovary	UBERON:0002118	99.27	gold quality
mucosa of stomach	UBERON:0001199	99.24	gold quality
lower esophagus mucosa	UBERON:0035834	99.22	gold quality
colonic epithelium	UBERON:0000397	99.19	gold quality
left ovary	UBERON:0002119	99.17	gold quality
omental fat pad	UBERON:0010414	99.13	gold quality
peritoneum	UBERON:0002358	99.12	gold quality
calcaneal tendon	UBERON:0003701	99.09	gold quality
rectum	UBERON:0001052	99.08	gold quality
monocyte	CL:0000576	99.07	gold quality

Single-cell (SCXA)

Detected in 26 experiment(s), a significant marker in 21.

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	59.67
E-MTAB-6701	yes	52.41
E-HCAD-4	yes	43.40
E-MTAB-8410	yes	38.55
E-HCAD-31	yes	33.70
E-HCAD-1	yes	32.77
E-MTAB-6678	yes	27.48
E-CURD-122	yes	25.06
E-MTAB-9221	yes	23.62
E-CURD-46	yes	13.60
E-MTAB-9067	yes	11.27
E-MTAB-5061	yes	11.14
E-HCAD-11	yes	10.25
E-CURD-112	yes	8.71
E-GEOD-130148	yes	7.84

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

78 targeting TPM4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-92A-2-5P	99.75	67.01	2164

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 19.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 21)

• Tm4-defined cytoskeleton is a marker of growth and repair/regeneration in response to injury, disease state and stress in skeletal muscle. (PMID:17968984)
• This protein has been found differentially expressed in the anterior cingulate cortex from patients with schizophrenia (PMID:20381070)
• Low TPM4 expression in the cytoplasm is associated with uterine cervix carcinogenesis. (PMID:21119665)
• TPM4, PDIA and SRC8 were also localized to the trophoblast cells, further highlighting the importance of these cytoskeletal remodelling proteins in early pregnancy (PMID:21373848)
• Plasma peroxiredoxins 1 and 2, and tropomyosin 4 were shown to associate with asbestos-exposure, and peroxiredoxin 1 with lung cancer. (PMID:22537621)
• In addition to CLIC1 and TPM1, which were the proteins initially discovered in a xenograft mouse model, CLIC4, TPM2, TPM3, and TPM4 were present in ovarian cancer patient sera at significantly elevated levels compared with controls. (PMID:23792823)
• Data indicate the upregulation of tropomyosin-4 in infiltrating ductal breast carcinomas (IDCAs) tissues, which may suggest its involvement in breast cancer development. (PMID:23812729)
• Results show that Tpm4.2 facilitates the transition of NM-2A to the strongly actin-binding myosin-ADP state. (PMID:26847712)
• In diabetes, expression of high molecular weight (HMW) isoforms from tropomyosin 1 (TPM1) were markedly decreased but HMW isoforms from tropomyosin 4 (TPM4) were not significantly different. (PMID:27649540)
• findings demonstrate a nonredundant role for TPM4 in platelet biogenesis in humans and mice and reveal that truncating variants in TPM4 cause a previously undescribed dominant Mendelian platelet disorder. (PMID:28134622)
• Tpm4.1 is essential to maintain cell-cell adhesions and to inhibit abnormal increases in cell migration and invasion, which are important to prevent invasion and metastasis of breast cancer cells. (PMID:28431393)
• TPM4 is associated with clinical progression in colon cancer patients and acts as a tumor suppressor in colon cancer cells. (PMID:29455030)
• Upregulation of tropomyosin alpha-4 chain in patients’ saliva with oral squamous cell carcinoma as demonstrated by Phage display. (PMID:31804537)
• Differential expression and diagnostic significance of P53, MutS homologs 2, tropomyosin-4 in alpha-fetoprotein-negative hepatocellular carcinoma. (PMID:32363617)
• TPM4 aggravates the malignant progression of hepatocellular carcinoma through negatively regulating SUSD2. (PMID:32432739)
• The expression and clinical significance of TPM4 in hepatocellular carcinoma. (PMID:33390785)
• The miR-133a, TPM4 and TAp63gamma Role in Myocyte Differentiation Microfilament Remodelling and Colon Cancer Progression. (PMID:34575979)
• Rare missense variants in Tropomyosin-4 (TPM4) are associated with platelet dysfunction, cytoskeletal defects, and excessive bleeding. (PMID:34758189)
• LncRNA SFTA1P promotes cervical cancer progression by interaction with PTBP1 to facilitate TPM4 mRNA degradation. (PMID:36344495)
• Integrated pan-cancer analysis and experimental verification of the roles of tropomyosin 4 in gastric cancer. (PMID:36993958)
• MicroRNA-5195-3p mediated malignant biological behaviour of insulin-resistant liver cancer cells via SOX9 and TPM4. (PMID:37328795)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	tpm4b	ENSDARG00000019128
danio_rerio	tpm4a	ENSDARG00000023963
mus_musculus	Tpm4	ENSMUSG00000031799
rattus_norvegicus	Tpm4	ENSRNOG00000015496
drosophila_melanogaster	Tm1	FBGN0003721
drosophila_melanogaster	Tm2	FBGN0004117
caenorhabditis_elegans	lev-11	WBGENE00002978

Paralogs (3): TPM1 (ENSG00000140416), TPM3 (ENSG00000143549), TPM2 (ENSG00000198467)

Protein

Protein identifiers

Tropomyosin alpha-4 chain — P67936 (reviewed: P67936)

Alternative names: TM30p1, Tropomyosin-4

All UniProt accessions (16): P67936, A0A2R8Y5V9, A0A2R8YE05, A0A2R8YEU4, A0A2R8YGX3, A0A2R8YHD2, A0A590UJB9, A0A590UK79, A0A590UKD0, A0A5F9UKJ4, A0A5F9UN72, K7ELP0, K7ENT6, K7EPB9, K7ERG3, V9HW56

UniProt curated annotations — full annotation on UniProt →

Function. Binds to actin filaments in muscle and non-muscle cells. Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction. Smooth muscle contraction is regulated by interaction with caldesmon. In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments. Binds calcium. Plays a role in platelet biogenesis.

Subunit / interactions. Homodimer. Heterodimer of an alpha (TPM1, TPM3 or TPM4) and a beta (TPM2) chain.

Subcellular location. Cytoplasm. Cytoskeleton.

Tissue specificity. Detected in cardiac tissue and platelets, the form found in cardiac tissue is a higher molecular weight than the form found in platelets. Expressed at higher levels in the platelets of hypertensive patients with cardiac hypertrophy than in the platelets of hypertensive patients without cardiac hypertrophy (at protein level).

Disease relevance. Bleeding disorder, platelet-type, 25 (BDPLT25) [MIM:620486] An autosomal dominant disorder characterized by increased bleeding tendency due to decreased or dysfunctional platelets. Platelet morphologic and functional defects are variable. Some individuals have normal numbers of enlarged platelets. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The molecule is in a coiled coil structure that is formed by 2 polypeptide chains. The sequence exhibits a prominent seven-residues periodicity.

Similarity. Belongs to the tropomyosin family.

Isoforms (2)

UniProt ID	Names	Canonical?
P67936-1	1	yes
P67936-2	2

RefSeq proteins (5): NP_001138632, NP_001354765, NP_001354766, NP_001354767, NP_003281* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000533	Tropomyosin	Family
IPR014751	XRCC4-like_C	Homologous_superfamily

Pfam: PF00261

UniProt features (19 total): sequence variant 5, modified residue 5, sequence conflict 3, initiator methionine 1, chain 1, splice variant 1, region of interest 1, coiled-coil region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P67936-F1	93.33	0.83

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (5): 2, 6, 177, 215, 216

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-390522	Striated Muscle Contraction
R-HSA-445355	Smooth Muscle Contraction
R-HSA-9013424	RHOV GTPase cycle
R-HSA-9725370	Signaling by ALK fusions and activated point mutants

MSigDB gene sets: 336 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, LIANG_HEMATOPOIESIS_STEM_CELL_NUMBER_SMALL_VS_HUGE_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, MORF_RAB5A, GGGNRMNNYCAT_UNKNOWN, JOHANSSON_GLIOMAGENESIS_BY_PDGFB_UP, GOBP_OSTEOBLAST_DIFFERENTIATION, CREBP1_Q2, TGACCTY_ERR1_Q2, CACCAGC_MIR138, LIEN_BREAST_CARCINOMA_METAPLASTIC, SP1_Q2_01, GOLDRATH_ANTIGEN_RESPONSE

GO Biological Process (4): osteoblast differentiation (GO:0001649), muscle contraction (GO:0006936), actin filament organization (GO:0007015), platelet formation (GO:0030220)

GO Molecular Function (9): calcium ion binding (GO:0005509), structural constituent of muscle (GO:0008307), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein heterodimerization activity (GO:0046982), actin filament binding (GO:0051015), actin binding (GO:0003779), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (11): stress fiber (GO:0001725), podosome (GO:0002102), cytosol (GO:0005829), cytoskeleton (GO:0005856), muscle thin filament tropomyosin (GO:0005862), actin filament (GO:0005884), focal adhesion (GO:0005925), membrane (GO:0016020), cortical cytoskeleton (GO:0030863), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Muscle contraction	2
RHO GTPase cycle	1
Signaling by ALK in cancer	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein dimerization activity	2
ossification	1
cell differentiation	1
muscle system process	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
myeloid cell differentiation	1
platelet morphogenesis	1
anatomical structure formation involved in morphogenesis	1
metal ion binding	1
structural molecule activity	1
protein binding	1
identical protein binding	1
actin binding	1
protein-containing complex binding	1
cytoskeletal protein binding	1
binding	1
cation binding	1
actomyosin	1
contractile actin filament bundle	1
actin-based cell projection	1
cytoplasm	1
intracellular membraneless organelle	1
striated muscle thin filament	1
protein-containing complex	1
actin cytoskeleton	1
polymeric cytoskeletal fiber	1
cell-substrate junction	1
cytoskeleton	1
cell cortex	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

177 interactions, top by confidence:

A	B	Type	Score
MYC	MAX	psi-mi:“MI:0914”(association)	0.980
PPP6C	ANKRD28	psi-mi:“MI:0914”(association)	0.870
PRKAG2	PRKAB2	psi-mi:“MI:0914”(association)	0.730
VSX1	USP12	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
TPM3	TPM4	psi-mi:“MI:0915”(physical association)	0.670
TPM4	TPM3	psi-mi:“MI:0914”(association)	0.670
TPM4	PICK1	psi-mi:“MI:0915”(physical association)	0.560
JRK	TPM4	psi-mi:“MI:0915”(physical association)	0.560
SNAPIN	TPM4	psi-mi:“MI:0915”(physical association)	0.560
ATF3	MYL6B	psi-mi:“MI:0914”(association)	0.530
KXD1	HIP1	psi-mi:“MI:0914”(association)	0.530
TPM4		psi-mi:“MI:0915”(physical association)	0.490
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
FOS	MYO1C	psi-mi:“MI:2364”(proximity)	0.480
PTP4A3	TPM4	psi-mi:“MI:0915”(physical association)	0.470

BioGRID (380): TPM4 (Affinity Capture-MS), TPM4 (Two-hybrid), LNX1 (Two-hybrid), TPM4 (Affinity Capture-MS), TPM4 (Affinity Capture-MS), TPM4 (Affinity Capture-MS), ACTN1 (Co-fractionation), ACTN2 (Co-fractionation), COX5A (Co-fractionation), OSTF1 (Co-fractionation), TPM4 (Co-fractionation), TPM4 (Co-fractionation), TPM4 (Co-fractionation), TPM4 (Co-fractionation), TPM4 (Co-fractionation)

ESM2 similar proteins: A1XQV4, A2V735, C5J049, O18416, O96764, O97192, P02561, P04268, P04692, P06753, P07951, P09491, P09493, P09495, P0DSM6, P0DSM7, P13104, P13105, P15846, P19352, P21107, P31816, P42637, P42639, P58771, P58772, P58773, P58774, P58775, P58776, P67936, P67937, P84335, Q01173, Q07068, Q1HPQ0, Q1HPU0, Q22866, Q23758, Q23939

Diamond homologs: A1XQV4, P02561, P04268, P04692, P06753, P07951, P09493, P13104, P13105, P19352, P21107, P42639, P58771, P58772, P58773, P58774, P58775, P58776, P67936, P67937, P84335, Q01173, Q07068, Q5KR47, Q5KR48, Q5KR49, P09495, Q63610, Q6IRU2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SMURF1	unknown	TPM4	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 191 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
RHO GTPases activate PKNs	5	12.6×	7e-03
Smooth Muscle Contraction	5	10.5×	8e-03
Apoptosis	6	8.0×	8e-03
Translocation of SLC2A4 (GLUT4) to the plasma membrane	6	7.3×	9e-03
Signaling by ALK fusions and activated point mutants	6	7.2×	1e-02
Programmed Cell Death	6	7.0×	1e-02
Diseases of signal transduction by growth factor receptors and second messengers	11	5.0×	5e-03
Signaling by Interleukins	9	4.6×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of miRNA transcription	6	10.8×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

58 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	33
Likely benign	4
Benign	2

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
2577543	NM_003290.3(TPM4):c.436C>T (p.Arg146Cys)	Pathogenic
2577544	NM_003290.3(TPM4):c.322C>T (p.Gln108Ter)	Pathogenic
2577545	NM_003290.3(TPM4):c.205C>T (p.Arg69Ter)	Pathogenic

SpliceAI

1704 predictions. Top by Δscore:

Variant	Effect	Δscore
19:16067735:GCAG:G	donor_gain	1.0000
19:16067736:CAG:C	donor_loss	1.0000
19:16067738:GGT:G	donor_loss	1.0000
19:16067739:G:C	donor_loss	1.0000
19:16067740:T:A	donor_loss	1.0000
19:16076041:CCCCA:C	acceptor_loss	1.0000
19:16076042:CCCA:C	acceptor_loss	1.0000
19:16076043:CCA:C	acceptor_loss	1.0000
19:16076044:CA:C	acceptor_loss	1.0000
19:16076045:A:AC	acceptor_loss	1.0000
19:16076045:A:AG	acceptor_gain	1.0000
19:16076045:AGGT:A	acceptor_gain	1.0000
19:16076046:G:GA	acceptor_loss	1.0000
19:16076046:G:GG	acceptor_gain	1.0000
19:16076046:GGT:G	acceptor_gain	1.0000
19:16076046:GGTG:G	acceptor_gain	1.0000
19:16076170:GAC:G	donor_gain	1.0000
19:16076173:G:GG	donor_gain	1.0000
19:16081908:CCCA:C	acceptor_loss	1.0000
19:16081910:CA:C	acceptor_loss	1.0000
19:16081911:A:AC	acceptor_loss	1.0000
19:16081911:AGGCT:A	acceptor_gain	1.0000
19:16081912:GGCT:G	acceptor_gain	1.0000
19:16081912:GGCTG:G	acceptor_gain	1.0000
19:16082042:GAGAG:G	donor_gain	1.0000
19:16082043:AGAGG:A	donor_loss	1.0000
19:16082044:GAG:G	donor_gain	1.0000
19:16082044:GAGGT:G	donor_loss	1.0000
19:16082045:AGG:A	donor_loss	1.0000
19:16082046:GGTA:G	donor_loss	1.0000

AlphaMissense

1625 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:16081953:T:C	L58P	1.000
19:16081989:T:C	L70P	1.000
19:16082010:T:C	L77P	1.000
19:16082018:G:C	A80P	1.000
19:16082030:G:C	A84P	1.000
19:16086448:G:C	A98P	1.000
19:16086491:T:C	L112P	1.000
19:16086499:G:C	A115P	1.000
19:16086511:G:C	A119P	1.000
19:16086520:G:C	A122P	1.000
19:16086527:G:C	R124P	1.000
19:16088040:T:C	L133P	1.000
19:16088081:G:C	A147P	1.000
19:16089071:T:C	L161P	1.000
19:16089092:T:C	L168P	1.000
19:16093684:G:C	A199P	1.000
19:16093696:G:C	A203P	1.000
19:16093705:G:C	A206P	1.000
19:16093727:T:C	L213P	1.000
19:16081935:T:C	L52P	0.999
19:16081941:G:C	R54P	0.999
19:16081944:G:C	R55P	0.999
19:16081976:G:C	A66P	0.999
19:16081997:G:C	A73P	0.999
19:16082001:T:C	L74P	0.999
19:16082027:G:C	A83P	0.999
19:16082046:G:C	R89T	0.999
19:16086423:A:C	R89S	0.999
19:16086423:A:T	R89S	0.999
19:16086446:G:C	R97P	0.999

dbSNP variants (sampled 300 via entrez): RS1000012430 (19:16074986 G>A,C), RS1000112794 (19:16092274 G>A), RS1000162675 (19:16095250 C>G,T), RS1000308941 (19:16070541 A>G,T), RS1000398960 (19:16093187 TTTG>T,TTTGTTG,TTTGTTGTTG), RS1000501234 (19:16096349 A>C), RS1000540545 (19:16089231 T>A,C), RS1000632490 (19:16066114 A>G), RS1000656677 (19:16088991 T>C,G), RS1000728978 (19:16089171 C>T), RS1000798971 (19:16103156 C>T), RS1000826311 (19:16082370 C>T), RS1000873039 (19:16078828 G>GT), RS1000925229 (19:16079068 G>A,C,T), RS1001099792 (19:16085120 G>A,C,T)

Disease associations

OMIM: gene MIM:600317 | disease phenotypes: MIM:620486

GenCC curated gene-disease

Disease	Classification	Inheritance
bleeding disorder, platelet-type, 25	Strong	Autosomal dominant
autosomal dominant macrothrombocytopenia	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
TPM4-related platelet disorder	Moderate	AD

Mondo (4): bleeding disorder, platelet-type, 25 (MONDO:0957580), hereditary breast ovarian cancer syndrome (MONDO:0003582), thrombocytopenia (MONDO:0002049), autosomal dominant macrothrombocytopenia (MONDO:0015372)

Orphanet (1): Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000132	Menorrhagia
HP:0000421	Epistaxis
HP:0000978	Bruising susceptibility
HP:0001873	Thrombocytopenia
HP:0004406	Spontaneous, recurrent epistaxis
HP:0004846	Prolonged bleeding after surgery
HP:0004866	Impaired ADP-induced platelet aggregation
HP:0006298	Prolonged bleeding after dental extraction
HP:0008320	Impaired collagen-induced platelet aggregation
HP:0011463	Childhood onset
HP:0011877	Increased mean platelet volume
HP:0011891	Post-partum hemorrhage
HP:0030138	Excessive bleeding from superficial cuts
HP:0032438	Platelet anisocytosis
HP:0040185	Macrothrombocytopenia
HP:0100608	Metrorrhagia

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST001335_2	Mean platelet volume	1.000000e-11
GCST001337_54	Platelet count	3.000000e-10
GCST001439_3	Mean platelet volume	3.000000e-09
GCST003383_13	Platelet count	2.000000e-08
GCST004599_144	Mean platelet volume	6.000000e-10
GCST004599_145	Mean platelet volume	1.000000e-67
GCST004603_192	Platelet count	6.000000e-16
GCST004603_193	Platelet count	4.000000e-61
GCST004607_16	Plateletcrit	7.000000e-22
GCST004616_42	Platelet distribution width	2.000000e-14
GCST004616_43	Platelet distribution width	2.000000e-58
GCST008047_3	Platelet count	5.000000e-10
GCST008336_2	Mean platelet volume	5.000000e-10
GCST012210_4	Longevity	1.000000e-06
GCST90002395_404	Mean platelet volume	7.000000e-21
GCST90002395_405	Mean platelet volume	2.000000e-177
GCST90002400_272	Plateletcrit	1.000000e-46
GCST90002401_256	Platelet distribution width	7.000000e-13
GCST90002401_257	Platelet distribution width	4.000000e-139
GCST90002402_619	Platelet count	8.000000e-12
GCST90002402_620	Platelet count	7.000000e-134

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0007985	platelet crit
EFO:0007984	platelet component distribution width

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295789 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.91	Kd	1220	nM	CHEMBL5653589
5.69	ED50	2042	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 5 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149644: Binding affinity to human TPM4 incubated for 45 mins by Kinobead based pull down assay	kd	1.2201	uM

CTD chemical–gene interactions

94 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases expression, decreases expression, increases abundance	6
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression, affects cotreatment	5
methylmercuric chloride	increases expression, affects cotreatment	4
bisphenol A	affects expression, decreases expression, increases expression, decreases reaction, increases abundance (+1 more)	4
trichostatin A	affects cotreatment, decreases expression, affects expression	4
Tretinoin	increases expression, decreases expression, affects cotreatment	4
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression, decreases expression	4
Cadmium Chloride	decreases methylation, increases methylation, increases expression, decreases expression	3
bisphenol F	increases expression, affects cotreatment, decreases expression	2
Acetaminophen	decreases expression, increases expression	2
Cisplatin	affects cotreatment, decreases expression, increases expression	2
Doxorubicin	affects expression	2
Estradiol	affects cotreatment, increases expression	2
Nickel	increases expression	2
Tobacco Smoke Pollution	increases expression, affects expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
ginger extract	decreases expression, decreases reaction, increases abundance, affects cotreatment, affects expression	1
geldanamycin	increases expression	1
urushiol	increases expression	1
bufotalin	decreases expression	1
alpha phellandrene	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pirinixic acid	affects binding, decreases expression, increases activity	1
deoxynivalenol	increases expression	1
potassium perchlorate	increases expression	1
arsenite	affects binding, decreases reaction	1
afimoxifene	affects response to substance	1
tetrabromobisphenol A	increases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118548	Binding	Binding affinity to TPM4 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3JZ	Abcam HEK293T TPM4 KO	Transformed cell line	Female

Clinical trials (associated diseases)

291 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00039858	PHASE4	COMPLETED	Evaluation of Argatroban Injection in Pediatric Patients Requiring Anticoagulant Alternatives to Heparin
NCT00239733	PHASE4	TERMINATED	Anti-D for Treating Thrombocytopenia in Adults Infected With Hepatitis C Virus With or Without HIV Co-Infection
NCT00907478	PHASE4	COMPLETED	Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP)
NCT01727401	PHASE4	TERMINATED	Thromboprophylaxis of Venous Thromboembolism in Acutely-ill Medical Inpatients With Thrombocytopenia
NCT02032134	PHASE4	TERMINATED	Protocol for the Infusion of Buffy Coat-derived Cryopreserved Platelets in Patients With Severe Thrombocytopenia
NCT02267993	PHASE4	COMPLETED	Efficacy and Safety of rhTPO for the Treatment of Thrombocytopenia After Chemotherapy in AML Patients
NCT03633019	PHASE4	UNKNOWN	High-dose Use of rhTPO in CIT Patients
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04906083	PHASE4	UNKNOWN	Avatrombopag in Patients With End-stage Liver Disease and Thrombocytopenia
NCT05217719	PHASE4	UNKNOWN	Effects of Recombinant Human Thrombopoietin on Platelet Levels in ICU Patients
NCT05255003	PHASE4	RECRUITING	STrategies for Anticoagulation in Patients With thRombocytopenia and Cancer-associated Thrombosis
NCT05382013	PHASE4	UNKNOWN	Efficacy and Safety of Avatrombopag for Treating TCP in HBV-ACLF Patients Receiving ALSS Treatment
NCT05944458	PHASE4	COMPLETED	Efficacy of Intravenous N-Acetylcysteine in Preventing Linezolid-Induced Thrombocytopenia in Critically Ill Patients
NCT06562738	PHASE4	RECRUITING	Clinical Study on Efficacy and Safety of Hetrombopag in the Preoperative Patients of Thrombocytopenia
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00037791	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00039910	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00073580	PHASE3	COMPLETED	Angiomax in Patients With HIT/HITTS Type II Undergoing Off-Pump Coronary Artery Bypass Grafting (CABG) (CHOOSE)
NCT00102323	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Refractory to Splenectomy
NCT00102336	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Prior to Splenectomy
NCT00116688	PHASE3	COMPLETED	Open Label Extension Study of Romiplostim (AMG 531) in Thrombocytopenic Patients With Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
NCT00128713	PHASE3	COMPLETED	Optimal Platelet Dose Strategy for Management of Thrombocytopenia
NCT00151866	PHASE3	COMPLETED	Efficacy of Transfusions With Platelets Stored in Platelet Additive Solution II Versus Plasma
NCT00261924	PHASE3	COMPLETED	Efficacy and Safety Study of Platelets Treated for Pathogen Inactivation and Stored for Up to Seven Days
NCT00415532	PHASE3	COMPLETED	Romiplostim (AMG 531) Versus Medical Standard of Care for Immune (Idiopathic) Thrombocytopenic Purpura
NCT00420914	PHASE3	TERMINATED	Strategies for Transfusion of Platelets (SToP)
NCT00501345	PHASE3	TERMINATED	Aspirin in Patients With Myocardial Infarction and Thrombocytopenia
NCT00508820	PHASE3	COMPLETED	An Open Label Study of Romiplostim in Adult Thrombocytopenic Subjects With ITP
NCT00678587	PHASE3	TERMINATED	Eltrombopag To Reduce The Need For Platelet Transfusion In Subjects With Chronic Liver Disease And Thrombocytopenia Undergoing Elective Invasive Procedures
NCT01438840	PHASE3	COMPLETED	Efficacy and Safety of Oral E5501 Plus Standard of Care for the Treatment of Thrombocytopenia in Adults With Chronic Immune Thrombocytopenia (Amendment 02)
NCT01444417	PHASE3	COMPLETED	Safety and Efficacy Study of Romiplostim to Treat Immune Thrombocytopenia (ITP) in Pediatric Patients
NCT01805648	PHASE3	UNKNOWN	Efficacy and Safety Study of Maintenance Treatment With rhTPO in Thrombocytopenic Subjects With ITP
NCT02244658	PHASE3	UNKNOWN	Recombinant Human Thrombopoietin (rhTPO) in Management of Chemotherapy-induced Thrombocytopenia in Acute Myelocytic Leukemia
NCT02389621	PHASE3	COMPLETED	Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures
NCT02444728	PHASE3	TERMINATED	Cyclophosphamide and Hydroxychloroquine for Thrombocytopenia in SLE
NCT02487563	PHASE3	COMPLETED	Prospective Study of Patients With Thrombocytopenia Following HSCT
NCT02578901	PHASE3	COMPLETED	American Trial Using Tranexamic Acid in Thrombocytopenia