NR5A1

nuclear receptor subfamily 5 group A member 1, the group of Nuclear receptor subfamily 5 group A

Basic information

Region (hg38): 9:124481236-124507420

Previous symbols: [ "FTZF1" ]

Links

ENSG00000136931 ∙ NCBI:2516 ∙ OMIM:184757 ∙ HGNC:7983 ∙ Uniprot:Q13285 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 46 XX gonadal dysgenesis (Supportive), mode of inheritance: AD
• 46,XY complete gonadal dysgenesis (Supportive), mode of inheritance: AD
• 46,XX ovotesticular disorder of sex development (Supportive), mode of inheritance: AD
• 46,XX sex reversal 1 (Supportive), mode of inheritance: AD
• 46,XY partial gonadal dysgenesis (Supportive), mode of inheritance: AD
• male infertility with azoospermia or oligozoospermia due to single gene mutation (Supportive), mode of inheritance: AD
• premature ovarian failure 7 (Strong), mode of inheritance: AD
• 46,XY sex reversal 3 (Strong), mode of inheritance: AD
• spermatogenic failure 8 (Limited), mode of inheritance: AD
• 46,XX sex reversal 4 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Adrenocortical insufficiency; 46,XX sex reversal 4; 46, XY sex reversal 3; Premature ovarian failure 7	AD/AR	Endocrine; Genitourinary; Obstetric; Oncologic	In adrenocortical insufficiency, which can manifest with severe electrolyte abnormalities and neurologic sequelae, recognition may allow beneficial medical management (eg, with hydrocortisone, fludrocortisone); In 46, XX and 46, XY sex reversal surgical removal of abdominal dysgenetic gonads and streak gonads is indicated due to increased risk of tumors; In 46, XY sex reversal, it has been suggested that early sperm cryopreservation may be beneficial for males to allow reproduction; Hormone replacement therapy may be beneficial in puberty; In Premature ovarian failure 7, genetic knowledge may be beneficial to allow Interventions such as preserving eggs in women with premature ovarian insufficiency	Endocrine; Genitourinary; Obstetric; Oncologic	1956279; 10369247; 11038323; 11932325; 15070943; 15579739; 15472171; 16439367; 16684822; 17200175; 17694559; 19246354; 19318730; 19439508; 19849982; 20301714; 20453312; 20861607; 20887963; 21163476; 21535007; 21654157; 21691975; 22028768; 22080441; 22474171; 22549935; 22907560; 22909003; 23044873; 23095176; 23096908; 23153500; 23168057; 23299922; 23543655; 23918653; 24067197; 24073220; 24157186; 24231572; 27378692; 27610946; 27490115; 27855412

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NR5A1 gene.

• 46,XY disorder of sex development;Oligosynaptic infertility (10 variants)
• 46,XY sex reversal 3 (9 variants)
• Oligosynaptic infertility;46,XY disorder of sex development (7 variants)
• not provided (4 variants)
• NR5A1-related disorder (2 variants)
• 46,XY partial gonadal dysgenesis (1 variants)
• 46,XX sex reversal 4 (1 variants)
• Male infertility with azoospermia or oligozoospermia due to single gene mutation (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NR5A1 gene is commonly pathogenic or not.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				28	10	38
missense	8	22	60	3	1	94
nonsense	10	4	1			15
start loss						0
frameshift	9	3				12
inframe indel		2	2			4
splice donor/acceptor (+/-2bp)	4	4	1			9
splice region		2	1	2		5
non coding	1		1	16	15	33
Total	32	35	65	47	26

Variants in NR5A1

This is a list of pathogenic ClinVar variants found in the NR5A1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
9-124481358-A-G		46,XY disorder of sex development;Oligosynaptic infertility	Benign (Dec 03, 2020)
9-124482584-AC-A			Benign (Jun 25, 2018)
9-124482676-G-A		46,XY disorder of sex development;Oligosynaptic infertility	Benign (Dec 03, 2020)
9-124482765-T-C			Uncertain significance (Jun 19, 2020)
9-124482765-T-G		Oligosynaptic infertility;46,XY disorder of sex development • Male infertility	Uncertain significance (Jan 16, 2024)
9-124482782-T-C		46,XY disorder of sex development;Oligosynaptic infertility	Likely benign (Jul 08, 2021)
9-124482791-C-T		46,XY disorder of sex development;Oligosynaptic infertility	Benign (Dec 13, 2023)
9-124482800-G-A		NR5A1-related disorder	Likely benign (May 30, 2019)
9-124482830-G-A		NR5A1-related disorder	Uncertain significance (Jun 26, 2019)
9-124482834-A-G		NR5A1-related disorder	Uncertain significance (Apr 19, 2024)
9-124482834-A-T		46,XY sex reversal 3	Pathogenic (Mar 01, 2007)
9-124482836-G-C		46,XY disorder of sex development;Oligosynaptic infertility	Uncertain significance (Jul 08, 2021)
9-124482837-T-C		Oligosynaptic infertility;46,XY disorder of sex development	Uncertain significance (Mar 29, 2019)
9-124482852-A-G		Inborn genetic diseases	Uncertain significance (Jan 30, 2024)
9-124482859-G-A		Oligosynaptic infertility;46,XY disorder of sex development	Benign (Nov 17, 2023)
9-124482861-GC-G			Likely pathogenic (Mar 29, 2018)
9-124482873-A-G		Inborn genetic diseases	Uncertain significance (Jun 07, 2023)
9-124482878-G-A		not specified	Conflicting classifications of pathogenicity (Jul 17, 2019)
9-124482911-G-A		Inborn genetic diseases	Likely benign (Jun 02, 2023)
9-124482917-G-C		46,XY disorder of sex development;Oligosynaptic infertility	Likely pathogenic (May 23, 2018)
9-124482921-T-G		Disorder of sexual differentiation	Pathogenic (Aug 15, 2021)
9-124482923-G-T		Oligosynaptic infertility;46,XY disorder of sex development	Pathogenic (May 29, 2022)
9-124482934-A-C		46,XY sex reversal 3	Pathogenic (May 27, 2014)
9-124482935-G-GTCAAGCAGGGCGGCGTTGGCCTTCTCCTGAGCGTCTT			Pathogenic (Jul 04, 2018)
9-124482939-A-G		46,XY disorder of sex development;Oligosynaptic infertility	Uncertain significance (Oct 06, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NR5A1	protein_coding	protein_coding	ENST00000373588	6	26194

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.990	0.0104	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.34	175	286	0.611	0.0000180	2931
Missense in Polyphen		21	88.991	0.23598		920
Synonymous	-0.203	141	138	1.02	0.00000948	946
Loss of Function	3.73	1	18.1	0.0551	7.83e-7	205

LoF frequencies by population

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

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcriptional activator. Essential for sexual differentiation and formation of the primary steroidogenic tissues (PubMed:27378692). Binds to the Ad4 site found in the promoter region of steroidogenic P450 genes such as CYP11A, CYP11B and CYP21B. Also regulates the AMH/Muellerian inhibiting substance gene as well as the AHCH and STAR genes. 5'-YCAAGGYC-3' and 5'- RRAGGTCA-3' are the consensus sequences for the recognition by NR5A1 (PubMed:27378692). The SFPQ-NONO-NR5A1 complex binds to the CYP17 promoter and regulates basal and cAMP-dependent transcriptional activity. Binds phosphatidylcholine (By similarity). Binds phospholipids with a phosphatidylinositol (PI) headgroup, in particular PI(3,4)P2 and PI(3,4,5)P3. Activated by the phosphorylation of NR5A1 by HIPK3 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation. {ECO:0000250|UniProtKB:P33242, ECO:0000269|PubMed:17210646, ECO:0000269|PubMed:27378692, ECO:0000269|PubMed:28459839}.
• Disease: DISEASE: 46,XY sex reversal 3 (SRXY3) [MIM:612965]: A condition characterized by male-to-female sex reversal in the presence of a normal 46,XY karyotype. {ECO:0000269|PubMed:10369247, ECO:0000269|PubMed:11932325, ECO:0000269|PubMed:17200175, ECO:0000269|PubMed:17694559, ECO:0000269|PubMed:24405868, ECO:0000269|PubMed:27378692, ECO:0000269|PubMed:27490115, ECO:0000269|PubMed:28459839}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 46,XX sex reversal 4 (SRXX4) [MIM:617480]: A condition in which male gonads develop in a genetic female (female to male sex reversal). {ECO:0000269|PubMed:27378692, ECO:0000269|PubMed:27490115, ECO:0000269|PubMed:27610946, ECO:0000269|PubMed:27855412}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Adrenal insufficiency, NR5A1-related (AINR) [MIM:612964]: A disorder characterized by adrenal insufficiency, muscular hypotonia, decreased sodium and increased potassium levels, elevated ACTH, salt-wasting crisis, prolonged jaundice, hypoglycemia, and vomiting. {ECO:0000269|PubMed:11038323, ECO:0000269|PubMed:26523528}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Premature ovarian failure 7 (POF7) [MIM:612964]: An ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol. {ECO:0000269|PubMed:19246354}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spermatogenic failure 8 (SPGF8) [MIM:613957]: An infertility disorder characterized by spermatogenesis failure and severe oligozoospermia. {ECO:0000269|PubMed:20887963}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Cortisol synthesis and secretion - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);NHR;Nuclear Receptors;Ovarian Infertility Genes;Gene expression (Transcription);Generic Transcription Pathway;Nuclear Receptor transcription pathway;RNA Polymerase II Transcription (Consensus)

Recessive Scores

• pRec: 0.680

Intolerance Scores

• loftool: 0.0125
• rvis_EVS: -0.05
• rvis_percentile_EVS: 50.22

Haploinsufficiency Scores

• pHI: 0.913
• hipred: Y
• hipred_score: 0.733
• ghis: 0.439

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nr5a1
• Phenotype: endocrine/exocrine gland phenotype; growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype

Zebrafish Information Network

• Gene name: nr5a1a
• Affected structure: endocrine pancreas
• Phenotype tag: abnormal
• Phenotype quality: malformed

Gene ontology

• Biological process: luteinization;transcription initiation from RNA polymerase II promoter;sex determination;primary sex determination;male gonad development;female gonad development;hormone-mediated signaling pathway;tissue development;multicellular organism aging;positive regulation of gene expression;cell differentiation;male sex determination;adrenal gland development;intracellular receptor signaling pathway;hormone metabolic process;steroid hormone mediated signaling pathway;positive regulation of transcription by RNA polymerase II;regulation of steroid biosynthetic process;maintenance of protein location in nucleus;response to gonadotropin-releasing hormone;calcineurin-mediated signaling;positive regulation of male gonad development;negative regulation of female gonad development
• Cellular component: nucleus;nucleoplasm;RNA polymerase II transcription factor complex
• Molecular function: transcription regulatory region sequence-specific DNA binding;RNA polymerase II regulatory region sequence-specific DNA binding;RNA polymerase II distal enhancer sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA binding;chromatin binding;steroid hormone receptor activity;transcription coactivator activity;nuclear receptor activity;protein binding;phospholipid binding;zinc ion binding;enzyme binding;sequence-specific DNA binding