KLHL3

kelch like family member 3, the group of Kelch like|BTB domain containing|MicroRNA protein coding host genes

Basic information

Region (hg38): 5:137617500-137736089

Links

ENSG00000146021 ∙ NCBI:26249 ∙ OMIM:605775 ∙ HGNC:6354 ∙ Uniprot:Q9UH77 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Transcripts

Transcript IDs starting with ENST are treated as Ensembl, all others as RefSeq. Showing 4 of 12.

Transcript ID	Protein ID	Coding exons	MANE Select	MANE Plus Clinical
NM_017415.3	NP_059111.2	15	yes	-
ENST00000309755.9	ENSP00000312397.4	15	yes	-
NM_001257194.1	NP_001244123.1	14	-	-
NM_001257195.2	NP_001244124.1	12	-	-

Phenotypes

GenCC

Source: genCC

• pseudohypoaldosteronism type 2D (Strong), mode of inheritance: AR
• pseudohypoaldosteronism type 2D (Strong), mode of inheritance: AD
• pseudohypoaldosteronism type 2D (Supportive), mode of inheritance: AD
• pseudohypoaldosteronism type 2D (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Pseudohypoaldosteronism, type IID	AD/AR	Renal	Treatment (eg, correction of physiologic abnormalities by thiazide diuretics) can be effective	Renal	22266938

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KLHL3 gene.

• not_provided (121 variants)
• Pseudohypoaldosteronism_type_2D (115 variants)
• Inborn_genetic_diseases (62 variants)
• Pseudohypoaldosteronism_type_2A (26 variants)
• not_specified (8 variants)
• KLHL3-related_disorder (8 variants)
• Renal_tubulopathies (3 variants)
• Cerebral_palsy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KLHL3 gene is commonly pathogenic or not. These statistics are base on transcript: NM_017415.3. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	29	5	39
missense	13	10	152			175
nonsense	4	2	1			7
start loss						0
frameshift	2					2
splice donor/acceptor (+/-2bp)	1		2			3
Total	20	12	160	29	5

Highest pathogenic variant AF is 0.000015489852

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KLHL3	protein_coding	protein_coding	ENST00000309755	15	118591

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
		125740	0	8	125748	0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.99	206	367	0.561	0.0000224	3862
Missense in Polyphen		61	148.48	0.41082		1420
Synonymous	0.751	134	146	0.921	0.00000957	1118
Loss of Function	4.35	5	31.2	0.160	0.00000141	366

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000578	0.0000578
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.00000902	0.00000879
Middle Eastern	0.0000544	0.0000544
South Asian	0.000131	0.000131
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of ion transport in the distal nephron (PubMed:14528312, PubMed:22406640, PubMed:23387299, PubMed:23453970, PubMed:23576762, PubMed:23665031). The BCR(KLHL3) complex acts by mediating ubiquitination of WNK4, an inhibitor of potassium channel KCNJ1, leading to WNK4 degradation (PubMed:23387299, PubMed:23453970, PubMed:23576762, PubMed:23665031). The BCR(KLHL3) complex also mediates ubiquitination and degradation of CLDN8, a tight-junction protein required for paracellular chloride transport in the kidney (By similarity). {ECO:0000250|UniProtKB:E0CZ16, ECO:0000269|PubMed:14528312, ECO:0000269|PubMed:22406640, ECO:0000269|PubMed:23387299, ECO:0000269|PubMed:23453970, ECO:0000269|PubMed:23576762, ECO:0000269|PubMed:23665031}.
• Disease: DISEASE: Pseudohypoaldosteronism 2D (PHA2D) [MIM:614495]: A disorder characterized by severe hypertension, hyperkalemia, hyperchloremia, hyperchloremic metabolic acidosis, and correction of physiologic abnormalities by thiazide diuretics. PHA2D inheritance is autosomal dominant or recessive. {ECO:0000269|PubMed:22266938, ECO:0000269|PubMed:22406640, ECO:0000269|PubMed:23387299, ECO:0000269|PubMed:23453970, ECO:0000269|PubMed:23576762, ECO:0000269|PubMed:23665031, ECO:0000269|PubMed:26435498, ECO:0000269|PubMed:27026694, ECO:0000269|PubMed:27780982, ECO:0000269|PubMed:28052936, ECO:0000269|PubMed:28511177}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Post-translational protein modification;Metabolism of proteins;Immune System;Adaptive Immune System;Antigen processing: Ubiquitination & Proteasome degradation;Class I MHC mediated antigen processing & presentation;Neddylation (Consensus)

Recessive Scores

• pRec: 0.110

Intolerance Scores

• loftool: 0.199
• rvis_EVS: -0.87
• rvis_percentile_EVS: 10.65

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.818

Gene Damage Prediction

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

Gene ontology

• Biological process: ubiquitin-dependent protein catabolic process;protein ubiquitination;post-translational protein modification;ion homeostasis;selective autophagy;renal sodium ion absorption;protein K48-linked ubiquitination;distal tubule morphogenesis
• Cellular component: cytosol;cytoskeleton;Cul3-RING ubiquitin ligase complex
• Molecular function: actin binding;structural molecule activity;protein binding