KLHL41
protein-codingkelch like family member 41, the group of Kelch like|BTB domain containing
Gene summary
This gene is a member of the kelch-like family. The encoded protein contains a BACK domain, a BTB/POZ domain, and 5 Kelch repeats. This protein is thought to function in skeletal muscle development and maintenance. Mutations in this gene have been associated with nemaline myopathy (NM), a rare congenital muscle disorder. [provided by RefSeq, Mar 2015]
- KBTBD10
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~16.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0015736
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015737
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014326
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0015738
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0015735
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014326
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014326
Submitter: ClinGen
*KLHL41* was first reported in relation to autosomal-recessive nemaline myopathy 9 in 2013 (Gupta VA, et al., PMID: 24268659). At least 8 unique variants (e.g. missense, in-frame indel, frameshift, large deletion) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Summary of Case Level Data: 3.5 POINTS. Variants in this gene have been curated from 5 probands in 3 publications ( PMID: 24268659, 28939701, 28749478). The mechanism for the disease is homozygous loss of function (PMID: 24268659). This gene-disease association is supported by a mouse model (PMID: 28826497) which recapitulates disease as well as a zebrafish myopathy model which was rescued by expression of human *KLHL41* (PMID: 24268659). Additionally, the function of KLHL41 in regulation of the thin filaments (PMIDs: 28826497, 30986853) its expression in skeletal muscle (PMID: 28826497), and its interaction with components of the sarcomere (PMID: 28826497), all provide further evidence. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the CM GCEP on 11/5/2019. It was reevaluated on 10/21/2024. As a result of this reevaluation no new evidence was identified and the classification remained at Moderate (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0014326
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal
Intervention: General
Rationale: 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to KLHL41 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006063.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 87 | 1 | 89 | ||
| missense | 1 | 1 | 176 | 10 | 1 | 189 |
| nonsense | 7 | 1 | 1 | 9 | ||
| start loss | 0 | |||||
| frameshift | 14 | 6 | 1 | 21 | ||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 22 | 9 | 179 | 97 | 2 | 309 |
Highest pathogenic variant AF is 0.000042773296
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006054.2 | 6 | MANE Select | |
| Ensembl | ENSP00000284669.1 | 6 | MANE Select | |
| Ensembl | ENSP00000616683.1 | 6 | Standard | |
| Ensembl | ENSP00000616683.1 | 6 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| klhl41a | Danio rerio | Structure: skeletal muscle Quality: refractivity abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Post-translational protein modification
- Metabolism of proteins
- Immune System
- Adaptive Immune System
- Antigen processing: Ubiquitination & Proteasome degradation
Biological Process
- striated muscle contraction
- protein ubiquitination
- myofibril assembly
- regulation of lateral pseudopodium assembly
- skeletal muscle cell differentiation
Molecular Function
- protein binding
Cellular Component
- ruffle
- nucleus
- cytoplasm
- endoplasmic reticulum membrane
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000284669
- Coding exons
- 6
- Length
- 16561
- Individuals with no LoFs
- 125704
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 44
- Defined
- 125748
- p
- 0.000175
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.887 | 282 | 327 | 0.862 | 0.0000172 | 3991 |
| Missense (PolyPhen) | 84 | 111.32 | 0.75457 | 1324 | ||
| Synonymous | 1.17 | 103 | 119 | 0.863 | 0.00000629 | 1179 |
| Loss of Function | 2.27 | 10 | 21.3 | 0.469 | 9.84e-7 | 299 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00019 | 0.00018 | rare |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.00025 | 0.00025 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in skeletal muscle development and differentiation. Regulates proliferation and differentiation of myoblasts and plays a role in myofibril assembly by promoting lateral fusion of adjacent thin fibrils into mature, wide myofibrils. Required for pseudopod elongation in transformed cells. {ECO:0000250|UniProtKB:A2AUC9}.;
- Disease
- DISEASE: Nemaline myopathy 9 (NEM9) [MIM:615731]: An autosomal recessive form of nemaline myopathy. Nemaline myopathies are muscular disorders characterized by muscle weakness of varying severity and onset, and abnormal thread-like or rod-shaped structures in muscle fibers on histologic examination. NEM9 phenotype is highly variable, ranging from death in infancy due to lack of antigravity movements, to slowly progressive distal muscle weakness with preserved ambulation later in childhood. {ECO:0000269|PubMed:24268659}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.124
Intolerance Scores
- RVIS EVS
- 0.2
- RVIS percentile EVS
- 67.3
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |