INSL3

protein-coding

insulin like 3, the group of Receptor ligands

Gene summary

This gene encodes a member of the insulin-like hormone superfamily. The encoded protein is mainly produced in gonadal tissues. Studies of the mouse counterpart suggest that this gene may be involved in the development of urogenital tract and female fertility. This protein may also act as a hormone to regulate growth and differentiation of gubernaculum, and thus mediating intra-abdominal testicular descent. Mutations in this gene may lead to cryptorchidism. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

Previous symbols:

RLNL

MANE transcript

NM_005543.4

Inheritance

ClinVar variants

P:7U:30B:7

Top phenotype

Cryptorchidism

gnomAD constraint

pLI —, LoF o/e 0.65

Max pathogenic AF

—

Genomic locus

chr19:17,816,512-17,821,574

External References & Databases

Ensembl (ENSG00000248099)

Transcript & Mutation Effects

hg38 • Region Span ~5.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cryptorchidismMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0009047

Submitter: PanelApp Australia

cryptorchidismMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0009047

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

CryptorchidismAD

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: 11095425; 12601553; 12970298; 17028442; 17437853; 19416190

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to INSL3 variants in ClinVar

6 Conditions Cataloged

Inborn genetic diseasesTotal: 27

not providedTotal: 7

CryptorchidismTotal: 7

not specifiedTotal: 5

INSL3-related disorderTotal: 5

Bilateral cryptorchidismTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005543.4. 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				1 clinvar		1
missense	3 clinvar		29 clinvar	5 clinvar	1 clinvar	38
nonsense	1 clinvar					1
start loss						0
frameshift	1 clinvar	2 clinvar				3
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	5	2	30	6	1	44

Highest pathogenic variant AF is 0.00047333466

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005543.4	RefSeq	NP_005534.2	2	MANE Select
ENST00000317306.8	Ensembl	ENSP00000321724.6	2	MANE Select
NM_001265587.2	RefSeq	NP_001252516.1	3	Standard
ENST00000379695.5	Ensembl	ENSP00000369017.4	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Relaxin signaling pathway - Homo sapiens (human)
MET in type 1 papillary renal cell carcinoma
Signaling by GPCR
Signal Transduction
G alpha (s) signalling events

Biological Process

G protein-coupled receptor signaling pathway
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway
cell-cell signaling
spermatogenesis
regulation of signaling receptor activity

Molecular Function

G protein-coupled receptor binding
protease binding
signaling receptor binding
insulin receptor binding
hormone activity

Cellular Component

extracellular region
extracellular space

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000379695
Coding exons: 3
Length: 5063
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	0.508	76	89.5	0.849	0.00000603	979
Missense (PolyPhen)		28	34.136	0.82024		307
Synonymous	-0.0303	42	41.8	1.01	0.00000337	341
Loss of Function	0.685	3	4.58	0.655	3.81e-7	40

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: Seems to play a role in testicular function. May be a trophic hormone with a role in testicular descent in fetal life. Is a ligand for LGR8 receptor.;

Recessive Scores

pRec: 0.113

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.914

Gene Damage Prediction

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