KLHL10

protein-coding

kelch like family member 10, the group of Kelch like|BTB domain containing

Gene summary

The protein encoded by this gene belongs to the kelch repeat-containing family, and contains an N-terminal BTB/POZ domain a BACK domain and six C-terminal kelch repeats. Kelch domains are thought to form a four stranded beta-sheet blade structure that can fold into a beta-propeller domain when multiple kelch repeats are found together. Mutations in this gene have been associated with oligozoospermia in some infertile males. [provided by RefSeq, Jul 2016]

MANE transcript

NM_152467.5

Inheritance

ClinVar variants

P:1U:57B:9

Top phenotype

Spermatogenic failure 11

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr17:41,835,685-41,848,384

External References & Databases

Ensembl (ENSG00000161594)

Transcript & Mutation Effects

hg38 • Region Span ~12.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

male infertility with azoospermia or oligozoospermia due to single gene mutationSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018393

Submitter: Orphanet

spermatogenic failure 11MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014037

Submitter: PanelApp Australia

spermatogenic failure 11LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014037

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Spermatogenic failure 11AD

Manifestation: Genitourinary

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: 17047026

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KLHL10 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 50

Spermatogenic failure 11Total: 9

not providedTotal: 8

KLHL10-related disorderTotal: 4

Non-obstructive azoospermiaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_152467.5. 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 clinvar	5 clinvar		6
missense	1 clinvar		55 clinvar	4 clinvar		60
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	1	0	57	9	0	67

Highest pathogenic variant AF is 0.000008673897

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_152467.5	RefSeq	NP_689680.2	5	MANE Select
ENST00000293303.5	Ensembl	ENSP00000293303.4	5	MANE Select
NM_001329595.1	RefSeq	NP_001316524.1	5	Standard
NM_001329596.2	RefSeq	NP_001316525.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

cell morphogenesis
spermatid development
male gonad development
fertilization
protein ubiquitination

Cellular Component

cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000293303
Coding exons: 5
Length: 12700
Individuals with no LoFs: 124799
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 124804
p: 0.0000200

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.72	213	358	0.595	0.0000209	4081
Missense (PolyPhen)		35	112.21	0.31192		1229
Synonymous	-0.789	143	131	1.09	0.00000831	1130
Loss of Function	3.80	2	20.6	0.0972	0.00000104	267

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000065	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be a substrate-specific adapter of a CUL3-based E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins during spermatogenesis.;
Disease: DISEASE: Spermatogenic failure 11 (SPGF11) [MIM:615081]: An infertility disorder caused by spermatogenesis defects. It results in decreased sperm motility, concentration, and multiple sperm structural defects. Oligozoospermia is usually observed in SPGF11 patients. In addition to oligozoospermia, teratozoospermia and moderate asthenozoospermia is observed in some cases. {ECO:0000269|PubMed:17047026}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.111

Intolerance Scores

LoFtool: 0.327
RVIS EVS: -0.03
RVIS percentile EVS: 51.92

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.200

Gene Damage Prediction

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