KIRREL3

protein-coding

kirre like nephrin family adhesion molecule 3, the group of I-set domain containing|C2-set domain containing|MicroRNA protein coding host genes

Gene summary

The protein encoded by this gene is a member of the nephrin-like protein family. These proteins are expressed in fetal and adult brain, and also in podocytes of kidney glomeruli. The cytoplasmic domains of these proteins interact with the C-terminus of podocin, also expressed in the podocytes, cells involved in ensuring size- and charge-selective ultrafiltration. The protein encoded by this gene is a synaptic cell adhesion molecule with multiple extracellular immunoglobulin-like domains and a cytoplasmic PDZ domain-binding motif. Mutations in this gene are associated with several neurological and cognitive disorders. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

MANE transcript

NM_032531.4

Inheritance

ClinVar variants

P:3U:134B:60

Top phenotype

Mental retardation, autosomal dominant 4

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr11:126,423,358-127,003,460

External References & Databases

Ensembl (ENSG00000149571)

Transcript & Mutation Effects

hg38 • Region Span ~580.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*KIRREL3* was first reported in relation to autosomal dominant intellectual disability (ID) in 2008 (Bhalla et al., PMID: 19012874). The authors found an individual with ID and a balanced translocation disrupting *KIRREL3* and *CDH15* and went on to identify five additional individuals with ID and *KIRREL3* missense variants of unknown inheritance. However, two of the three unique variants had an allele frequency in gnomAD too high to be considered pathogenic. Since then, additional individuals with *KIRREL3* missense variants and neurodevelopmental disorders (NDD), including ID, autism, and seizures, have been reported in the literature; at least 5 were *de novo* (PMIDs: 25363760, 25363768, 28714951, 32503885, 33853164), but 8 were inherited from an unaffected parent (PMIDs: 27824329, 29271092). None of the missense variants were scored due to their presence in gnomAD and/or inheritance from reportedly unaffected parents and a lack of evidence of pathogenicity. Additionally, 3 probands with truncating variants have been reported: one with a de novo variant and ID (PMID: 26411299) and 2 with an inherited variant and ASD (PMID: 37007974). KIRREL3 is not constrained for truncating variants (pLI = 0, gnomAD v4.0.0) or missense variants (Z = 1.59). Therefore, the truncating variants were also not scored. KIRREL3 is a synaptic cell adhesion protein shown to be required for synapse formation in the rodent hippocampus (PMIDs: 26575286, 28670619). Functional in vitro studies of five *KIRREL3* missense variants observed in affected individuals showed decreased synapse formation in hippocampal neurons (PMID: 32503885); however, at least two of these variants were observed at a high frequency in gnomAD, questioning the relevance of this assay for the neurodevelopmental phenotypes observed in humans. While studies in homozygous null Kirrel3-/- mice and synapse deficits in cultured Kirrel3+/- mouse hippocampal neurons suggest that *KIRREL3* plays a role in central nervous system development, none of the experimental evidence was scored due to the lack of compelling genetic evidence. In summary, the evidence supporting the relationship between *KIRREL3* and complex neurodevelopmental disorder has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role of *KIRREL3* in this disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 8, 2023 (SOP Version 10).

intellectual developmental disorder, autosomal dominant 4LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0012947

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorderNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: PanelApp Australia

autosomal dominant non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015802

Submitter: Orphanet

intellectual developmental disorder, autosomal dominant 4LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012947

Submitter: G2P

Clinical Genomic Database (CGD)

Mental retardation, autosomal dominant 4AD

Manifestation: Craniofacial; Musculoskeletal; 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: 19012874

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KIRREL3 variants in ClinVar

12 Conditions Cataloged

not specifiedTotal: 137

not providedTotal: 64

KIRREL3-related disorderTotal: 19

Intellectual disability, autosomal dominant 4Total: 6

Autism spectrum disorderTotal: 2

Difficulty walkingTotal: 1

Absent speechTotal: 1

Global developmental delayTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032531.4. 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			3 clinvar	40 clinvar	6 clinvar	49
missense		2 clinvar	121 clinvar	11 clinvar	2 clinvar	136
nonsense			4 clinvar	1 clinvar		5
start loss						0
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)		1 clinvar	3 clinvar			4
Total	0	3	134	52	8	197

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032531.4	RefSeq	NP_115920.1	17	MANE Select
ENST00000525144.7	Ensembl	ENSP00000435466.2	17	MANE Select
NM_001161707.2	RefSeq	NP_001155179.1	14	Standard
NM_001301097.2	RefSeq	NP_001288026.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Primary Focal Segmental Glomerulosclerosis FSGS
Nephrin family interactions
Cell-Cell communication

Biological Process

neuron migration
inter-male aggressive behavior
homophilic cell adhesion via plasma membrane adhesion molecules
synapse assembly
principal sensory nucleus of trigeminal nerve development

Molecular Function

protein binding

Cellular Component

extracellular region
plasma membrane
integral component of membrane
axon
dendrite

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000525144
Coding exons: 17
Length: 580102
Individuals with no LoFs: 124734
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 124744
p: 0.0000401

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.35	343	490	0.701	0.0000321	4990
Missense (PolyPhen)		127	212.85	0.59666		2098
Synonymous	0.745	200	214	0.935	0.0000160	1559
Loss of Function	4.75	6	37.3	0.161	0.00000185	424

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000084	0.000064	rare
Latino/Admixed American	0.000032	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000064	0.000062	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Synaptic adhesion molecule required for the formation of target-specific synapses. Required for formation of target- specific synapses at hippocampal mossy fiber synapses. Required for formation of mossy fiber filopodia, the synaptic structures connecting dentate granule and GABA neurons. Probably acts as a homophilic adhesion molecule that promotes trans-cellular interactions and stabilize mossy fiber filipodia contact and subsequent synapse formation. Required for the coalescence of vomeronasal sensory neuron axons. May be involved in the hematopoietic supportive capacity of stroma cells; the secreted extracellular domain is directly responsible for supporting hematopoietic stem cells. {ECO:0000250|UniProtKB:Q8BR86}.;
Disease: DISEASE: Note=A chromosomal aberration involving KIRREL3 and CDH15 is found in a patient with severe mental retardation and dysmorphic facial features. Translocation t(11;16)(q24.2;q24). {ECO:0000269|PubMed:19012874}.;

Intolerance Scores

LoFtool: 0.151
RVIS EVS: -1.39
RVIS percentile EVS: 4.27

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.211

Gene Damage Prediction

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