SOX3

SRY-box transcription factor 3, the group of SRY-box transcription factors

Basic information

Region (hg38): X:140502985-140505069

Previous symbols: [ "PHP" ]

Links

ENSG00000134595 ∙ NCBI:6658 ∙ OMIM:313430 ∙ HGNC:11199 ∙ Uniprot:P41225 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 46,XX sex reversal 3 (Definitive), mode of inheritance: XLD
• intellectual disability, X-linked, with panhypopituitarism (Definitive), mode of inheritance: XLR
• septooptic dysplasia (Supportive), mode of inheritance: AD
• 46,XX sex reversal 1 (Supportive), mode of inheritance: AD
• X-linked intellectual disability with isolated growth hormone deficiency (Supportive), mode of inheritance: XL
• X-linked congenital generalized hypertrichosis (Supportive), mode of inheritance: XL
• panhypopituitarism (Supportive), mode of inheritance: AR
• panhypopituitarism, X-linked (Limited), mode of inheritance: XL
• intellectual disability, X-linked, with panhypopituitarism (Limited), mode of inheritance: XL
• 46,XX sex reversal 3 (Definitive), mode of inheritance: XL
• intellectual disability, X-linked, with panhypopituitarism (Definitive), mode of inheritance: XL
• panhypopituitarism, X-linked (Strong), mode of inheritance: XL
• SOX3-related X-linked pituitary hormone deficiency with or without intellectual developmental disorder (Moderate), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Intellectual developmental disorder, X-linked, with panyhypopituitarism; Panhypopituitarism, X-linked	XL	Endocrine	Treatment for endocrine deficiencies, including those resulting in neonatal electrolyte abnormalities, may be beneficial	Endocrine; Musculoskeletal; Neurologic	8826446; 9106538; 11031100; 12428212; 15800844; 16167084; 17400794; 21183788
Deletions/insertions involving SOX3 regulatory regions can result in 46,XX sex reversal 3 (XL) or Hypoparathyroidism, X-linked by a position effect (XL)

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SOX3 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SOX3 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			1	15	4	20
missense			36	5	3	44
nonsense						0
start loss						0
frameshift						0
inframe indel			4	11		15
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding			1	1		2
Total	0	0	42	32	7

Variants in SOX3

This is a list of pathogenic ClinVar variants found in the SOX3 region.

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

Position	Type	Phenotype	Significance	ClinVar
X-140503715-G-A		SOX3-related disorder	Likely benign (Jan 18, 2022)
X-140503764-C-A		Premature ovarian insufficiency	Uncertain significance (Jan 10, 2018)
X-140503796-C-T		Intellectual disability, X-linked, with panhypopituitarism	Uncertain significance (Feb 06, 2023)
X-140503825-G-C			Benign/Likely benign (Nov 01, 2023)
X-140503873-G-A		SOX3-related disorder	Likely benign (Apr 05, 2019)
X-140503952-A-G			Uncertain significance (Jun 10, 2022)
X-140503968-T-G			Likely benign (Nov 14, 2018)
X-140503972-GGCTGCGGCCGCA-G			Likely benign (Oct 01, 2023)
X-140503977-C-T		not specified	Uncertain significance (May 16, 2023)
X-140503984-AGCTGCGGCCGCGGCGGTG-A		SOX3-related disorder	Uncertain significance (Jul 17, 2023)
X-140503987-T-C		SOX3-related disorder	Likely benign (Aug 28, 2024)
X-140503993-C-T			Likely benign (Jul 14, 2017)
X-140504001-T-G		not specified	Uncertain significance (Jul 13, 2021)
X-140504005-G-T		SOX3-related disorder	Likely benign (Oct 28, 2019)
X-140504032-G-A		SOX3-related disorder	Likely benign (Jan 07, 2022)
X-140504032-G-C		not specified	Likely benign (May 16, 2023)
X-140504053-C-T		not specified	Uncertain significance (Feb 16, 2023)
X-140504057-C-A			Uncertain significance (Apr 01, 2023)
X-140504074-G-A			Likely benign (Jun 27, 2018)
X-140504093-A-G		not specified	Likely benign (Apr 07, 2023)
X-140504095-G-C			Uncertain significance (Oct 20, 2021)
X-140504105-C-T		not specified	Uncertain significance (Sep 27, 2022)
X-140504115-C-T		SOX3-related disorder	Likely benign (Sep 12, 2023)
X-140504120-G-C			Uncertain significance (Mar 01, 2023)
X-140504134-G-A			Likely benign (Sep 04, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SOX3	protein_coding	protein_coding	ENST00000370536	1	2074

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.449	0.525	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.21	76	153	0.497	0.0000101	2786
Missense in Polyphen		23	79.217	0.29034		1316
Synonymous	1.11	57	68.7	0.830	0.00000494	997
Loss of Function	1.79	1	5.54	0.180	3.50e-7	101

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: Transcription factor required during the formation of the hypothalamo-pituitary axis. May function as a switch in neuronal development. Keeps neural cells undifferentiated by counteracting the activity of proneural proteins and suppresses neuronal differentiation. Required also within the pharyngeal epithelia for craniofacial morphogenesis. Controls a genetic switch in male development. Is necessary for initiating male sex determination by directing the development of supporting cell precursors (pre-Sertoli cells) as Sertoli rather than granulosa cells (By similarity). {ECO:0000250, ECO:0000269|PubMed:21183788}.
• Disease: DISEASE: Panhypopituitarism X-linked (PHPX) [MIM:312000]: Affected individuals have absent infundibulum, anterior pituitary hypoplasia, and ectopic posterior pituitary. {ECO:0000269|PubMed:15800844}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mental retardation, X-linked, with isolated growth hormone deficiency (MRXGH) [MIM:300123]: A disorder characterized by the association of variable degrees of mental retardation with panhypopituitarism, variable combinations of hypothyroidism, delayed pubertal development, and short stature due to growth hormone deficiency. {ECO:0000269|PubMed:12428212}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 46,XX sex reversal 3 (SRXX3) [MIM:300833]: A condition in which male gonads develop in a genetic female (female to male sex reversal). {ECO:0000269|PubMed:21183788}. Note=The disease is caused by mutations affecting the gene represented in this entry. Copy number variations (CNV) encompassing or in close proximity to SOX3 are responsible for XX male reversal. These variations include two duplications of approximately 123 kb and 85 kb, the former of which spans the entire SOX3 gene; a 343 kb deletion immediately upstream of SOX3 that is probably responsible of altered regulation (and not increased dosage) of SOX3; a large (approximately 6 Mb) duplication that encompasses SOX3 and at least 18 additional distally located genes. Its proximal breakpoint falls within the SOX3 regulatory region. This large rearrangement has been found in a patient with XX male reversal and a complex phenotype that also includes a scrotal hypoplasia, microcephaly, developmental delay, and growth retardation.
• Pathway: Signaling by WNT;Signal Transduction;Deactivation of the beta-catenin transactivating complex;TCF dependent signaling in response to WNT (Consensus)

Recessive Scores

• pRec: 0.399

Haploinsufficiency Scores

• pHI: 0.983

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.539

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Sox3
• Phenotype: skeleton 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); reproductive system 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); homeostasis/metabolism phenotype; cellular phenotype; craniofacial phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype

Zebrafish Information Network

• Gene name: sox3
• Affected structure: epibranchial ganglion
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: regulation of transcription, DNA-templated;regulation of transcription by RNA polymerase II;central nervous system development;sensory organ development;sex determination;hypothalamus development;pituitary gland development;cell differentiation;neuron differentiation;negative regulation of neuron differentiation;face development;negative regulation of nucleic acid-templated transcription
• Cellular component: nucleus;nucleoplasm;nuclear transcription factor complex
• Molecular function: RNA polymerase II core promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA binding;transcription corepressor activity