KLHL40

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

Basic information

Region (hg38): 3:42685536-42692544

Previous symbols: [ "KBTBD5" ]

Links

ENSG00000157119 ∙ NCBI:131377 ∙ OMIM:615340 ∙ HGNC:30372 ∙ Uniprot:Q2TBA0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• nemaline myopathy 8 (Definitive), mode of inheritance: AR
• nemaline myopathy 8 (Strong), mode of inheritance: AR
• nemaline myopathy 8 (Moderate), mode of inheritance: AR
• severe congenital nemaline myopathy (Supportive), mode of inheritance: AR
• nemaline myopathy 8 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Nemaline myopathy 8	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	Musculoskeletal	23746549

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KLHL40 gene.

• Nemaline myopathy 8 (412 variants)
• not provided (78 variants)
• Inborn genetic diseases (40 variants)
• not specified (22 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KLHL40 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			4	106	5	115
missense	1	4	240	5	6	256
nonsense	7	5				12
start loss						0
frameshift	7	1	1			9
inframe indel			6		1	7
splice donor/acceptor (+/-2bp)	2	5			1	8
splice region			5	4		9
non coding				26	8	34
Total	17	15	251	137	21

Highest pathogenic variant AF is 0.0000263

Variants in KLHL40

This is a list of pathogenic ClinVar variants found in the KLHL40 region.

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

Position	Type	Phenotype	Significance	ClinVar
3-42685605-C-G		not specified	Likely benign (Aug 24, 2017)
3-42685624-G-T		Nemaline myopathy 8	Likely benign (Jan 20, 2023)
3-42685631-T-C		Nemaline myopathy 8	Likely benign (Nov 14, 2023)
3-42685632-TGGAGCAGGCGGA-T		Nemaline myopathy 8	Uncertain significance (Jul 21, 2021)
3-42685634-G-A		Inborn genetic diseases	Uncertain significance (Sep 14, 2022)
3-42685640-G-A		Nemaline myopathy 8	Uncertain significance (Jun 03, 2022)
3-42685641-C-T		Nemaline myopathy 8	Uncertain significance (Oct 25, 2022)
3-42685643-G-T		Nemaline myopathy 8	Likely pathogenic (Jun 20, 2019)
3-42685653-G-C		Nemaline myopathy 8	Uncertain significance (Aug 12, 2022)
3-42685667-A-G		Inborn genetic diseases	Uncertain significance (Dec 27, 2023)
3-42685670-C-G		Nemaline myopathy 8	Uncertain significance (Dec 11, 2023)
3-42685676-C-T		Nemaline myopathy 8	Pathogenic (Mar 18, 2022)
3-42685681-C-T		Nemaline myopathy 8	Likely benign (Jun 14, 2023)
3-42685695-T-G		Nemaline myopathy 8	Uncertain significance (Jun 27, 2022)
3-42685699-G-A		Nemaline myopathy 8	Likely benign (Jan 08, 2022)
3-42685703-C-T		Nemaline myopathy 8	Uncertain significance (Jul 06, 2022)
3-42685704-A-G		Nemaline myopathy 8	Uncertain significance (Sep 06, 2022)
3-42685706-G-A		Nemaline myopathy 8	Uncertain significance (May 17, 2023)
3-42685711-G-T		Nemaline myopathy 8	Uncertain significance (Jul 06, 2022)
3-42685715-C-T		Nemaline myopathy 8 • Inborn genetic diseases	Conflicting classifications of pathogenicity (Oct 13, 2023)
3-42685717-C-T		Nemaline myopathy 8	Likely benign (Aug 17, 2023)
3-42685718-G-C		Nemaline myopathy 8	Conflicting classifications of pathogenicity (Aug 25, 2021)
3-42685722-G-A		Nemaline myopathy 8	Uncertain significance (Sep 01, 2021)
3-42685723-T-C		Nemaline myopathy 8	Likely benign (Sep 07, 2022)
3-42685726-G-A		Nemaline myopathy 8	Likely benign (Nov 13, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KLHL40	protein_coding	protein_coding	ENST00000287777	6	7026

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000354	0.947	125726	0	22	125748	0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.0218	420	421	0.997	0.0000282	4024
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000150	0.000149
Ashkenazi Jewish	0.00	0.00
East Asian	0.000336	0.000217
Finnish	0.0000478	0.0000462
European (Non-Finnish)	0.000127	0.000105
Middle Eastern	0.000336	0.000217
South Asian	0.00	0.00
Other	0.000164	0.000163

dbNSFP

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

Haploinsufficiency Scores

• pHI: 0.502
• hipred: Y
• hipred_score: 0.707
• ghis: 0.545

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Klhl40
• Phenotype: muscle phenotype; cellular phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); growth/size/body region 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)

Zebrafish Information Network

• Gene name: klhl40b
• Affected structure: skeletal muscle
• Phenotype tag: abnormal
• Phenotype quality: loose

Gene ontology

• 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;skeletal muscle fiber differentiation
• Cellular component: cytoplasm;Cul3-RING ubiquitin ligase complex;A band;I band