LMOD3

Chr 3

leiomodin 3

Also known as: NEM10

NCBI Gene: 56203 ENSG00000163380 UniProt: Q0VAK6

This protein catalyzes actin nucleation and organizes sarcomeric thin filaments in skeletal muscle through its three actin-binding domains and other structural motifs that localize to the pointed ends of thin filaments. Mutations cause nemaline myopathy 10, inherited in an autosomal recessive pattern, which presents as a severe congenital form characterized by nonprogressive generalized muscle weakness and nemaline body inclusions in skeletal muscle fibers. The pathogenic mechanism involves dominant-negative effects that disrupt normal thin filament organization.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is a member of the leiomodin family of proteins. This protein contains three actin-binding domains, a tropomyosin domain, a leucine-rich repeat domain, and a Wiskott-Aldrich syndrome protein homology 2 domain (WH2). Localization of this protein to the pointed ends of thin filaments has been observed, and there is evidence that this protein acts as a catalyst of actin nucleation, and is important to the organization of sarcomeric thin filaments in skeletal muscles. Mutations in this gene have been associated as one cause of Nemaline myopathy, as other genes have also been linked to this disorder. Nemaline myopathy is a disorder characterized by nonprogressive generalized muscle weakness and protein inclusions (nemaline bodies) in skeletal myofibers. Patients with mutations in this gene often present with a severe congenital form of the disorder. [provided by RefSeq, Jan 2015]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtNemaline myopathy 10

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · nemaline myopathy 10 · AR · ClinGen 2019

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.14

LOEUF

LOF

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.14LOEUF

pLI 0.000

Z-score 1.12

OE 0.72 (0.47–1.14)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.62Z-score

OE missense 1.10 (1.00–1.21)

331 obs / 300.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.72 (0.47–1.14)

0≤0.351.4

Missense OE?1.10 (1.00–1.21)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 13 / 18.2Missense obs/exp: 331 / 300.8Syn Z: -1.30

Background carrier burden — how many people carry a rare variant somewhere in LMOD3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 44

812 rare PASS variants

Rare truncating (LoF)

1 in 2,000

108 rare PASS variants

Rare synonymous (reference)

1 in 130

305 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for LMOD3. 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 77	1 in 2,600
South Asian	~43k	1 in 75	1 in 680
Remaining (unassigned)	~30k	1 in 65	1 in 1,800
European (Finnish)	~27k	1 in 310	≈ 1 in 13,000
Admixed American	~22k	1 in 51	1 in 870
African / African American	~21k	1 in 55	1 in 1,200
East Asian	~20k	1 in 78	1 in 760
Ashkenazi Jewish	~13k	1 in 520	≈ 1 in 4,300
Middle Eastern	~2,884	1 in 49	≈ 1 in 2,900

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 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓