SOX17
protein-codingSRY-box transcription factor 17, the group of SRY-box transcription factors
Gene summary
This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~3.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013356
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0013356
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013356
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013356
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0017329
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015924
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0015924
Submitter: ClinGen
*SOX17* was first reported in relation to autosomal dominant pulmonary arterial hypertension (PAH) as a part of the UK NIHR PAH cohort study (PMID:30527956). Since then, subsequent studies have confirmed the role of *SOX17* in PAH. *SOX17* encodes a transcription factor specific to endothelial cells which is believed to play an important role in cardiovascular development (PMID:36205124). Twenty-one variants (13 missense, 1 nonsense, 7 frameshift) reported in 23 IPAH probands in 6 publications (PMIDs: 29650961, 30029678, 30044643, 30578397, 33952808, 31727138) are included in this curation. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by expression studies and in vitro functional assays (PMIDs:24153254, 33952808, 29650961). Graf et al. observed SOX17 protein predominantly located within the endothelial cells of plexiform lesions in the lung samples of patients with PAH (PMID:29650961). Furthermore, Corado et al. reported exclusive expression of SOX17 in the endothelial pulmonary arterioles of mice (PMID:24153254). Finally, Wang et al. created a *SOX17* mutant construct (p.Gln127Ter) in COS-7 cells. The *SOX17* variant resulted in a repression of *NOTCH-1* activation and then rescued by a WT copy of *SOX17.* In summary, *SOX17* is definitively associated with autosomal dominant PAH. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen PAH Gene Curation Expert Panel on the meeting date 08/30/22 (SOP Version 9). SOX17-related PAH may also include congenital heart disease (CHD). On January 2, 2024, the CHD GCEP independently evaluated SOX17 for PAH that includes CHD. Types of cardiac anomalies found in affected individuals with SOX17 variants include atrial septal defect, ventricular septal defect, and atrioventricular canal defect. Nineteen variants (missense, nonsense, frameshift) identified in at least 20 PAH-CHD probands have been reported (PMIDs: 30029678, 33794346, 35618278, 37895315). SOX17-related PAH-CHD is associated with an earlier onset than isolated PAH.
Clinical Genomic Database (CGD)
Manifestation: Renal
Intervention: Renal
Rationale: Monitoring and intervention related to vesicoureteral reflux may be beneficial in terms of helping to preserve renal function
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SOX17 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_022454.4. 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 | 51 | 6 | 60 | ||
| missense | 7 | 169 | 18 | 1 | 195 | |
| nonsense | 1 | 2 | 3 | |||
| start loss | 0 | |||||
| frameshift | 1 | 4 | 5 | |||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 2 | 7 | 178 | 69 | 7 | 263 |
Highest pathogenic variant AF is 0.0000065698705
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_071899.1 | 2 | MANE Select | |
| Ensembl | ENSP00000297316.4 | 2 | MANE Select | |
| Ensembl | ENSP00000805198.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| sox17 | Danio rerio | Structure: erythroid lineage cell Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Wnt signaling pathway - Homo sapiens (human)
- Cardiac Progenitor Differentiation
- Endoderm Differentiation
- Mesodermal Commitment Pathway
- Wnt Signaling Pathway
Biological Process
- negative regulation of transcription by RNA polymerase II
- angiogenesis
- vasculogenesis
- endoderm formation
- inner cell mass cellular morphogenesis
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription activator activity, RNA polymerase II-specific
- transcription coactivator activity
- protein binding
- beta-catenin binding
Cellular Component
- nucleus
- nucleoplasm
- transcription factor complex
- nuclear transcription factor complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000297316
- Coding exons
- 2
- Length
- 2954
- 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 | 0.774 | 199 | 232 | 0.857 | 0.0000107 | 2618 |
| Missense (PolyPhen) | 86 | 110.83 | 0.776 | 1264 | ||
| Synonymous | -1.36 | 122 | 104 | 1.17 | 0.00000521 | 855 |
| Loss of Function | 2.86 | 1 | 11.4 | 0.0876 | 5.00e-7 | 118 |
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:
- Function
- FUNCTION: Acts as transcription regulator that binds target promoter DNA and bends the DNA. Binds to the sequences 5'- AACAAT-'3 or 5'-AACAAAG-3'. Modulates transcriptional regulation via WNT3A. Inhibits Wnt signaling. Promotes degradation of activated CTNNB1. Plays a key role in the regulation of embryonic development. Required for normal looping of the embryonic heart tube. Required for normal development of the definitive gut endoderm. Probable transcriptional activator in the premeiotic germ cells (By similarity). {ECO:0000250}.;
Recessive Scores
- pRec
- 0.226
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.726
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |