KLHL15

protein-coding

kelch like family member 15, the group of Kelch like|BTB domain containing

Gene summary

This gene encodes a member of the kelch-like family of proteins that share a common domain structure consisting of an N-terminal broad-complex, tramtrack, bric-a-brac/poxvirus and zinc finger domain and C-terminal kelch repeat motifs. The encoded protein may be involved in protein ubiquitination and cytoskeletal organization. [provided by RefSeq, Apr 2009]

MANE transcript

NM_030624.3

Inheritance

XL, AD

ClinVar variants

P:6U:124B:32

Top phenotype

Intellectual developmental disorder, X-linked 103

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:23,983,716-24,027,186

External References & Databases

Ensembl (ENSG00000174010)

Transcript & Mutation Effects

hg38 • Region Span ~43.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, X-linked 103STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010508

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, X-linked 103MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010508

Submitter: PanelApp Australia

intellectual developmental disorder, X-linked 103LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0010508

Submitter: Ambry Genetics

intellectual developmental disorder, X-linked 103LIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0010508

Submitter: G2P

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked 103XL

Manifestation: Craniofacial; Neurologic

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: 24817631; 25644381

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KLHL15 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 59

not specifiedTotal: 48

Intellectual disability, X-linked 103Total: 16

KLHL15-related disorderTotal: 12

Abnormal brain morphologyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_030624.3. 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			8 clinvar	26 clinvar	3 clinvar	37
missense	1 clinvar	1 clinvar	108 clinvar	3 clinvar		113
nonsense		1 clinvar	5 clinvar			6
start loss						0
frameshift	1 clinvar	2 clinvar	3 clinvar			6
splice donor/acceptor (+/-2bp)						0
Total	2	4	124	29	3	162

Highest pathogenic variant AF is 9.106282e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_030624.3	RefSeq	NP_085127.2	2	MANE Select
ENST00000328046.8	Ensembl	ENSP00000332791.8	2	MANE Select
ENST00000684871.1	Ensembl	ENSP00000509774.1	2	Standard
ENST00000685367.1	Ensembl	ENSP00000509439.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

ubiquitin-dependent protein catabolic process
protein ubiquitination
nuclear protein quality control by the ubiquitin-proteasome system
negative regulation of double-strand break repair via homologous recombination

Molecular Function

protein binding

Cellular Component

nucleus
Cul3-RING ubiquitin ligase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000328046
Coding exons: 2
Length: 43467
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.69	84	247	0.340	0.0000196	4025
Missense (PolyPhen)		19	84.289	0.22542		1313
Synonymous	-0.105	99	97.7	1.01	0.00000831	1152
Loss of Function	3.63	0	15.3	0.00	0.00000126	247

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Substrate-specific adapter for CUL3 E3 ubiquitin-protein ligase complex (PubMed:14528312). Acts as an adapter for CUL3 to target the serine/threonine-protein phosphatase 2A (PP2A) subunit PPP2R5B for ubiquitination and subsequent proteasomal degradation, thus promoting exchange with other regulatory subunits (PubMed:23135275). Acts as an adapter for CUL3 to target the DNA- end resection factor RBBP8/CtIP for ubiquitination and subsequent proteasomal degradation. Through the regulation of RBBP8/CtIP protein turnover, plays a key role in DNA damage response, favoring DNA double-strand repair through error-prone non- homologous end joining (NHEJ) over error-free, RBBP8-mediated homologous recombination (HR) (PubMed:27561354). {ECO:0000269|PubMed:14528312, ECO:0000269|PubMed:23135275, ECO:0000269|PubMed:27561354}.;
Disease: DISEASE: Mental retardation, X-linked 103 (MRX103) [MIM:300982]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. {ECO:0000269|PubMed:24817631, ECO:0000269|PubMed:25644381}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.111

Intolerance Scores

RVIS EVS: -0.38
RVIS percentile EVS: 27.42

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.731

Gene Damage Prediction

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