KLHL40

protein-coding

kelch like family member 40, the group of BTB domain containing|Kelch like

Gene summary

This gene encodes a protein containing a BACK domain, a BTB/POZ domain, and 5 Kelch repeats, however, its exact function is not known. The gene and the multi-domain protein structure are conserved across different taxa, including primates, rodents, chicken and zebrafish. [provided by RefSeq, Dec 2012]

Previous symbols:

KBTBD5

MANE transcript

NM_152393.4

Inheritance

ClinVar variants

P:56U:301B:181

Top phenotype

Nemaline myopathy 8

gnomAD constraint

pLI —, LoF o/e 0.57

Max pathogenic AF

—

Genomic locus

chr3:42,685,537-42,692,544

External References & Databases

Ensembl (ENSG00000157119)

Transcript & Mutation Effects

hg38 • Region Span ~7.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nemaline myopathy 8MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014138

Submitter: Ambry Genetics

nemaline myopathy 8DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014138

Submitter: ClinGen

KLHL40 was first reported in relation to autosomal recessive nemaline myopathy 8 in 2013 (Ravenscroft G, et al., PMID: 23746549). At least 26 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 17 probands in 4 publications (PMIDs: 23746549, 26754003, 28973083, 27528495). Variants in this gene segregated with disease in 5 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. This gene-disease association is supported by its exclusive expression in skeletal muscle which is altered in patients, its biochemical function in stabilization of LMOD3 and protein interaction with NEB, as well as zebrafish and mouse models which recapitulate disruption of muscle structures and loss of movement, and a rescue of the mouse model with muscle-specific wild type KLHL40. In summary, KLHL40 is definitively associated with autosomal recessive nemaline myopathy 8. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

nemaline myopathy 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014138

Submitter: PanelApp Australia

nemaline myopathy 8DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014138

Submitter: G2P

severe congenital nemaline myopathySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015735

Submitter: Orphanet

nemaline myopathy 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014138

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Nemaline myopathy 8AR

Manifestation: 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

Refs: 23746549

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KLHL40 variants in ClinVar

6 Conditions Cataloged

Nemaline myopathy 8Total: 496

Inborn genetic diseasesTotal: 128

not providedTotal: 100

not specifiedTotal: 26

KLHL40-related disorderTotal: 21

KLHL40-related disordersTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_152393.4. 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			4 clinvar	161 clinvar	5 clinvar	170
missense	4 clinvar	11 clinvar	293 clinvar	12 clinvar	3 clinvar	323
nonsense	11 clinvar	10 clinvar	1 clinvar			22
start loss						0
frameshift	11 clinvar	2 clinvar	2 clinvar			15
splice donor/acceptor (+/-2bp)	2 clinvar	5 clinvar	1 clinvar			8
Total	28	28	301	173	8	538

Highest pathogenic variant AF is 0.000059197235

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_152393.4	RefSeq	NP_689606.2	6	MANE Select
ENST00000287777.5	Ensembl	ENSP00000287777.4	6	MANE Select
ENST00000942345.1	Ensembl	ENSP00000612404.1	5	Standard
ENST00000942345.2	Ensembl	ENSP00000612404.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
klhl40b	Danio rerio	Structure: skeletal muscle Quality: loose abnormal

Gene / Model

Organism

Observed Phenotype

klhl40b

Danio rerio

Structure: skeletal muscle

Quality: loose

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of protein ubiquitination
positive regulation of protein ubiquitination
negative regulation of proteasomal ubiquitin-dependent protein catabolic process
positive regulation of proteasomal ubiquitin-dependent protein catabolic process
skeletal muscle fiber development

Cellular Component

cytoplasm
Cul3-RING ubiquitin ligase complex
A band
I band

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000287777
Coding exons: 6
Length: 7026
Individuals with no LoFs: 125726
Homozygous LoFs: 0
Heterozygous LoFs: 22
Defined: 125748
p: 0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0218	420	421	0.997	0.0000282	4024
Missense (PolyPhen)		125	126.26	0.99003		1243
Synonymous	0.143	190	193	0.987	0.0000142	1285
Loss of Function	1.83	12	21.0	0.570	8.98e-7	250

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00034	0.00022	rare
Finnish	0.000048	0.000046	rare
European (Non-Finnish)	0.00013	0.00011	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a key regulator of skeletal muscle development (PubMed:23746549). The BCR(KLHL40) complex acts by mediating ubiquitination and degradation of TFDP1, thereby regulating the activity of the E2F:DP transcription factor complex (By similarity). Promotes stabilization of LMOD3 by acting as a negative regulator of LMOD3 ubiquitination; the molecular process by which it negatively regulates ubiquitination of LMOD3 is however unclear (By similarity). {ECO:0000250|UniProtKB:Q9D783, ECO:0000269|PubMed:23746549}.;

Intolerance Scores

RVIS EVS: -0.91
RVIS percentile EVS: 10.12

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