TPM3

Chr 1ADAR

tropomyosin 3

Also known as: CAPM1, CFTD, CMYO4A, CMYO4B, CMYP4A, CMYP4B, HEL-189, HEL-S-82p

NCBI Gene: 7170 ENSG00000143549 UniProt: P06753 OMIM: 191030

The protein stabilizes actin filaments and regulates access of other actin-binding proteins as part of the cytoskeletal structure. Mutations cause autosomal dominant nemaline myopathy and other congenital myopathies, with both autosomal dominant and autosomal recessive inheritance patterns observed. The pathogenic mechanism involves dominant-negative effects that disrupt normal cytoskeletal function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the tropomyosin family of actin-binding proteins. Tropomyosins are dimers of coiled-coil proteins that provide stability to actin filaments and regulate access of other actin-binding proteins. Mutations in this gene result in autosomal dominant nemaline myopathy and other muscle disorders. This locus is involved in translocations with other loci, including anaplastic lymphoma receptor tyrosine kinase (ALK) and neurotrophic tyrosine kinase receptor type 1 (NTRK1), which result in the formation of fusion proteins that act as oncogenes. There are numerous pseudogenes for this gene on different chromosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Congenital myopathy 4A, autosomal dominantMIM #255310

Congenital myopathy 4B, autosomal recessiveMIM #609284

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · TPM3-related myopathy · AD · ClinGen 2024

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.69

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.69LOEUF

pLI 0.007

Z-score 2.56

OE 0.37 (0.21–0.69)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.35Z-score

OE missense 0.45 (0.37–0.55)

65 obs / 144.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.37 (0.21–0.69)

0≤0.351.4

Missense OE?0.45 (0.37–0.55)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 7 / 19.0Missense obs/exp: 65 / 144.7Syn Z: 0.24

Background carrier burden — how many people carry a rare variant somewhere in TPM3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 290

292 rare PASS variants

Rare truncating (LoF)

1 in 4,200

47 rare PASS variants

Rare synonymous (reference)

1 in 460

148 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TPM3. 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 650	1 in 4,200
South Asian	~43k	1 in 190	1 in 5,600
Remaining (unassigned)	~30k	1 in 480	1 in 4,300
European (Finnish)	~27k	1 in 620	1 in 5,100
Admixed American	~22k	1 in 270	1 in 2,300
African / African American	~21k	1 in 570	1 in 2,600
East Asian	~20k	1 in 560	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 710	none seen
Middle Eastern	~2,884	1 in 170	none seen

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): 9 of 10 coding exons well covered in gnomAD exomes; exon 7 marginal. Genomes: all 10.? see exons ↓