TPM3

tropomyosin 3, the group of Tropomyosins

Basic information

Region (hg38): 1:154155307-154194648

Previous symbols: [ "NEM1" ]

Links

ENSG00000143549 ∙ NCBI:7170 ∙ OMIM:191030 ∙ HGNC:12012 ∙ Uniprot:P06753 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• congenital fiber-type disproportion myopathy (Moderate), mode of inheritance: Semidominant
• congenital myopathy 4B, autosomal recessive (Moderate), mode of inheritance: Semidominant
• congenital fiber-type disproportion myopathy (Supportive), mode of inheritance: AD
• intermediate nemaline myopathy (Supportive), mode of inheritance: AD
• childhood-onset nemaline myopathy (Supportive), mode of inheritance: AD
• cap myopathy (Supportive), mode of inheritance: AD
• congenital generalized hypercontractile muscle stiffness syndrome (Supportive), mode of inheritance: AD
• congenital myopathy 4B, autosomal recessive (Strong), mode of inheritance: AR
• congenital myopathy 4A, autosomal dominant (Strong), mode of inheritance: AD
• TPM3-related myopathy (Definitive), mode of inheritance: Semidominant

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Congenital myopathy 4A, autosomal dominant; Congenital myopathy 4B, autosomal recessive	AD/AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Craniofacial; Musculoskeletal	18300303; 10619715; 12196661; 18382475

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TPM3 gene.

• Congenital myopathy with fiber type disproportion (156 variants)
• Congenital myopathy 4B, autosomal recessive (131 variants)
• Congenital myopathy 4B, autosomal recessive;Congenital myopathy with fiber type disproportion (78 variants)
• not provided (68 variants)
• Congenital myopathy with fiber type disproportion;Congenital myopathy 4B, autosomal recessive (43 variants)
• Nemaline myopathy (25 variants)
• not specified (13 variants)
• Congenital myopathy 4A, autosomal dominant (4 variants)
• Inborn genetic diseases (3 variants)
• TPM3-related myopathy (1 variants)
• See cases (1 variants)
• Myopathy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TPM3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	24		26
missense	4	10	58	2		74
nonsense						0
start loss						0
frameshift		1	1			2
inframe indel			4			4
splice donor/acceptor (+/-2bp)			4			4
splice region			8	11		19
non coding		1	100	43	22	166
Total	4	12	169	69	22

Variants in TPM3

This is a list of pathogenic ClinVar variants found in the TPM3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-154158721-G-A			Likely benign (Jun 14, 2018)
1-154161840-C-A		Congenital myopathy 4B, autosomal recessive • Congenital myopathy with fiber type disproportion	Uncertain significance (Jan 12, 2018)
1-154162011-A-G		Congenital myopathy with fiber type disproportion • Congenital myopathy 4B, autosomal recessive	Uncertain significance (Jan 12, 2018)
1-154162036-C-G		Congenital myopathy 4B, autosomal recessive • Congenital myopathy with fiber type disproportion	Uncertain significance (Jan 13, 2018)
1-154162067-T-A		Congenital myopathy 4B, autosomal recessive • Congenital myopathy with fiber type disproportion	Uncertain significance (Jan 13, 2018)
1-154162072-T-C		Congenital myopathy 4B, autosomal recessive • Congenital myopathy with fiber type disproportion	Uncertain significance (Mar 23, 2018)
1-154162081-A-C		Nemaline myopathy • Congenital myopathy with fiber type disproportion	Benign (Jun 14, 2016)
1-154162142-G-A		Congenital myopathy with fiber type disproportion • Congenital myopathy 4B, autosomal recessive	Uncertain significance (Jan 12, 2018)
1-154162182-T-C		Congenital myopathy 4B, autosomal recessive • Congenital myopathy with fiber type disproportion	Uncertain significance (Jan 13, 2018)
1-154162222-G-A		Congenital myopathy 4B, autosomal recessive • Congenital myopathy with fiber type disproportion	Uncertain significance (Jan 12, 2018)
1-154162236-G-A		Congenital myopathy 4B, autosomal recessive • Congenital myopathy with fiber type disproportion	Likely benign (Jan 13, 2018)
1-154162279-C-T		Congenital myopathy 4B, autosomal recessive • Congenital myopathy with fiber type disproportion	Uncertain significance (Jan 13, 2018)
1-154162297-G-A		Congenital myopathy 4B, autosomal recessive • Congenital myopathy with fiber type disproportion	Conflicting classifications of pathogenicity (Jan 12, 2018)
1-154162343-C-A		Congenital myopathy with fiber type disproportion • Congenital myopathy 4B, autosomal recessive	Conflicting classifications of pathogenicity (Jan 13, 2018)
1-154162354-G-A		Congenital myopathy 4B, autosomal recessive • Congenital myopathy with fiber type disproportion	Uncertain significance (Jan 12, 2018)
1-154162360-G-A		Nemaline myopathy • Congenital myopathy with fiber type disproportion	Uncertain significance (Jun 14, 2016)
1-154162360-GTC-G		Nemaline myopathy • Congenital myopathy with fiber type disproportion	Uncertain significance (Jun 14, 2016)
1-154162364-C-CA		Nemaline myopathy • Congenital myopathy with fiber type disproportion	Uncertain significance (Jun 14, 2016)
1-154162384-AAC-A		Nemaline myopathy • Congenital myopathy with fiber type disproportion	Uncertain significance (Jun 14, 2016)
1-154162437-G-C		Congenital myopathy 4B, autosomal recessive • Congenital myopathy with fiber type disproportion	Uncertain significance (Jan 13, 2018)
1-154162497-T-G		Congenital myopathy with fiber type disproportion • Congenital myopathy 4B, autosomal recessive	Uncertain significance (Jan 12, 2018)
1-154162500-C-T		Congenital myopathy 4B, autosomal recessive • Congenital myopathy with fiber type disproportion	Uncertain significance (Jan 12, 2018)
1-154162531-T-C		Congenital myopathy with fiber type disproportion • Congenital myopathy 4B, autosomal recessive	Uncertain significance (Jan 13, 2018)
1-154162671-A-C		Congenital myopathy with fiber type disproportion • Congenital myopathy 4B, autosomal recessive	Uncertain significance (Jan 13, 2018)
1-154162698-G-A		Congenital myopathy with fiber type disproportion • Congenital myopathy 4B, autosomal recessive	Uncertain significance (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TPM3	protein_coding	protein_coding	ENST00000368530	10	39341

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00665	0.990	125729	0	19	125748	0.0000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.35	65	145	0.449	0.00000845	1887
Missense in Polyphen		25	60.882	0.41063		801
Synonymous	0.243	50	52.2	0.957	0.00000273	491
Loss of Function	2.56	7	19.0	0.368	0.00000104	249

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000145	0.000145
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000474	0.0000462
European (Non-Finnish)	0.000115	0.000105
Middle Eastern	0.0000544	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: 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. {ECO:0000250|UniProtKB:P09493}.
• Disease: DISEASE: Nemaline myopathy 1 (NEM1) [MIM:609284]: A form of nemaline myopathy with autosomal dominant or recessive inheritance. Nemaline myopathies are disorders characterized by muscle weakness of varying onset and severity, and abnormal thread-like or rod-shaped structures in muscle fibers on histologic examination. Autosomal dominant NEM1 is characterized by a moderate phenotype with onset between birth and early second decade of life. Weakness is diffuse and symmetric with slow progression often with need for a wheelchair in adulthood. The autosomal recessive form has onset at birth with moderate to severe hypotonia and diffuse weakness. In the most severe cases, death can occur before 2 years. Less severe cases have delayed major motor milestones, and these patients may walk, but often need a wheelchair before 10 years. {ECO:0000269|PubMed:10587521, ECO:0000269|PubMed:17376686, ECO:0000269|PubMed:24692096, ECO:0000269|PubMed:7704029}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A chromosomal aberration involving TPM3 is found in papillary thyroid carcinomas (PTCs). A rearrangement with NTRK1 generates the TRK fusion transcript by fusing the amino end of isoform 2 of TPM3 to the 3'-end of NTRK1. {ECO:0000269|PubMed:2869410}.; DISEASE: Myopathy, congenital, with fiber-type disproportion (CFTD) [MIM:255310]: A genetically heterogeneous disorder in which there is relative hypotrophy of type 1 muscle fibers compared to type 2 fibers on skeletal muscle biopsy. However, these findings are not specific and can be found in many different myopathic and neuropathic conditions. {ECO:0000269|PubMed:18300303, ECO:0000269|PubMed:19953533, ECO:0000269|PubMed:20951040, ECO:0000269|PubMed:24692096}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cap myopathy 1 (CAPM1) [MIM:609284]: A rare congenital skeletal muscle disorder characterized by the presence of cap-like structures which are well demarcated and peripherally located under the sarcolemma and show abnormal accumulation of sarcomeric proteins. Clinical features are early onset of hypotonia and slowly progressive muscle weakness. Respiratory problems are common. {ECO:0000269|PubMed:18300303, ECO:0000269|PubMed:19487656, ECO:0000269|PubMed:19553118, ECO:0000269|PubMed:24239060, ECO:0000269|PubMed:24692096}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Cardiac muscle contraction - Homo sapiens (human);Dilated cardiomyopathy (DCM) - Homo sapiens (human);Hypertrophic cardiomyopathy (HCM) - Homo sapiens (human);Adrenergic signaling in cardiomyocytes - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Thyroid cancer - Homo sapiens (human);miR-targeted genes in epithelium - TarBase;miR-targeted genes in leukocytes - TarBase;miR-targeted genes in lymphocytes - TarBase;miR-targeted genes in muscle cell - TarBase;miR-targeted genes in squamous cell - TarBase;Striated Muscle Contraction;Smooth Muscle Contraction;Striated Muscle Contraction;Muscle contraction (Consensus)

Recessive Scores

• pRec: 0.466

Intolerance Scores

• loftool: 0.0953
• rvis_EVS: 0.3
• rvis_percentile_EVS: 72.01

Haploinsufficiency Scores

• pHI: 0.578
• hipred: Y
• hipred_score: 0.668

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: K
• gene_indispensability_pred: E
• gene_indispensability_score: 0.964

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tpm3
• Phenotype: mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); muscle phenotype

Zebrafish Information Network

• Gene name: tpm3
• Affected structure: slow muscle cell
• Phenotype tag: abnormal
• Phenotype quality: decreased thickness

Gene ontology

• Biological process: muscle contraction;actin filament organization;muscle filament sliding
• Cellular component: stress fiber;cytosol;cytoskeleton;muscle thin filament tropomyosin;actin filament;actin cytoskeleton;extracellular exosome
• Molecular function: molecular_function;protein binding;actin filament binding