GeneBe

SOX10

protein-coding

SRY-box transcription factor 10, 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 activator after forming a protein complex with other proteins. This protein acts as a nucleocytoplasmic shuttle protein and is important for neural crest and peripheral nervous system development. Mutations in this gene are associated with Waardenburg-Shah and Waardenburg-Hirschsprung disease. [provided by RefSeq, Jul 2008]

MANE transcript

NM_006941.4

Inheritance

AD

ClinVar variants

P:248U:170B:138

Top phenotype

Waardenburg syndrome, type 4C; Waardenburg syndrome, type 2E; Peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease; Hirschsprung disease, susceptibility to, 10

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr22:37,970,686-37,987,422

External References & Databases

Ensembl (ENSG00000100146)NCBI Gene (6663)OMIM (602229)HGNC:11190GenCCUniProt (P56693)AlphaFoldClinVar (SOX10)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~16.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Waardenburg syndrome type 2EDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012698

Submitter: G2P

deaf blind hypopigmentation syndrome, Yemenite typeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011133

Submitter: G2P

PCWH syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012198

Submitter: Ambry Genetics

Waardenburg syndrome type 2ESTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012698

Submitter: Labcorp Genetics (formerly Invitae)

Waardenburg syndrome type 4CDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013202

Submitter: Ambry Genetics

Waardenburg-Shah syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019518

Submitter: Orphanet

PCWH syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012198

Submitter: PanelApp Australia

Waardenburg syndrome type 4CDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013202

Submitter: ClinGen

The SOX10 gene has been associated with autosomal dominant Waardenburg syndrome using the ClinGen Clinical Validity Framework as of 8/9/2017. This association was made using case-level data only. At least 8 variants (missense, nonsense, insertions, deletions) have been reported in humans. SOX10 was first associated with this disease in humans as early as 1998 (Pingault et al.). Association is seen in at least 9 probands, 8 of which are de novo, in 6 publications (9462749, 18348274, 27863645, 24735604, 27240497, 24311220). Variants in this gene segregated with disease in 2 additional family members. This gene-disease association is supported by relevant experimental evidence including animal models, expression studies, in vitro functional assays, and protein interactions. In summary, SOX10 is definitively associated with autosomal dominant Waardenburg syndrome. This classification was approved by the ClinGen Hearing Loss Working Group on 6/19/2018.

Waardenburg syndrome type 2SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019517

Submitter: Orphanet

Waardenburg syndrome type 2ESTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012698

Submitter: PanelApp Australia

PCWH syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012198

Submitter: G2P

PCWH syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012198

Submitter: Orphanet

Kallmann syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018800

Submitter: Orphanet

Waardenburg syndrome type 4CSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013202

Submitter: PanelApp Australia

Waardenburg syndrome type 4CDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013202

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Clinical Genomic Database (CGD)

Waardenburg syndrome, type 4C; Waardenburg syndrome, type 2E; Peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease; Hirschsprung disease, susceptibility to, 10AD

Manifestation: Audiologic/Otolaryngologic; Dermatologic; Gastrointestinal; Genitourinary; Neurologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic; Gastrointestinal

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; In some individuals (such as with Peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease), awareness of potential GI complications (eg, chronic intestinal pseudoobstruction) may be beneficial to allow prompt and appropriate management

Comments: Variants affecting regulatory regions have been implicated in Hirschsprung disease

Refs: 8911608; 9462749; 10441344; 10077527; 12189494; 17999358; 18348267; 18627047; 22246888; 24357527Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SOX10 variants in ClinVar

24 Conditions Cataloged
not providedTotal: 328
Waardenburg syndrome type 4CTotal: 120
SOX10-related disorderTotal: 73
not specifiedTotal: 72
Waardenburg syndrome type 2ETotal: 60
PCWH syndromeTotal: 54
Inborn genetic diseasesTotal: 30
Waardenburg syndromeTotal: 21

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006941.4. 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.

EffectPLPVUSLBBSum
synonymous
5
clinvar
97
clinvar
1
clinvar
 103
missense
15
clinvar
45
clinvar
154
clinvar
35
clinvar
5
clinvar
 254
nonsense
43
clinvar
17
clinvar
2
clinvar
 62
start loss
1
clinvar
1
clinvar
 2
frameshift
67
clinvar
45
clinvar
7
clinvar
 119
splice donor/acceptor (+/-2bp)
7
clinvar
7
clinvar
2
clinvar
 16
Total1331151701326556

Highest pathogenic variant AF is 0.0000023088112

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_006941.4RefSeqNP_008872.13MANE Select
ENST00000396884.8EnsemblENSP00000380093.23MANE Select
ENST00000360880.6EnsemblENSP00000354130.23Standard
ENST00000360880.7EnsemblENSP00000354130.23Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
sox10Danio rerio

Structure: hematopoietic multipotent progenitor cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Neural Crest Differentiation

Biological Process

  • in utero embryonic development
  • neural crest cell migration
  • morphogenesis of an epithelium
  • positive regulation of neuroblast proliferation
  • regulation of transcription by RNA polymerase II

Molecular Function

  • RNA polymerase II proximal promoter sequence-specific DNA binding
  • RNA polymerase II distal enhancer sequence-specific DNA binding
  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • DNA-binding transcription activator activity, RNA polymerase II-specific
  • DNA binding

Cellular Component

  • chromatin
  • nucleus
  • nucleoplasm
  • extrinsic component of mitochondrial outer membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000396884
Coding exons
3
Length
16737
Individuals with no LoFs
121460
Homozygous LoFs
0
Heterozygous LoFs
1
Defined
121461
p
0.00000412
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.771663010.5510.00001952969
Missense (PolyPhen)41112.620.364051146
Synonymous1.011301460.8930.0000112965
Loss of Function3.51014.30.006.53e-7173

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.00000920.0000092rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Transcription factor that plays a central role in developing and mature glia. Specifically activates expression of myelin genes, during oligodendrocyte (OL) maturation, such as DUSP15 and MYRF, thereby playing a central role in oligodendrocyte maturation and CNS myelination. Once induced, MYRF cooperates with SOX10 to implement the myelination program. Transcriptional activator of MITF, acting synergistically with PAX3 (PubMed:21965087). {ECO:0000250|UniProtKB:Q04888, ECO:0000269|PubMed:21965087}.;
Disease
DISEASE: Waardenburg syndrome 4C (WS4C) [MIM:613266]: A disorder characterized by the association of Waardenburg features (depigmentation and deafness) with the absence of enteric ganglia in the distal part of the intestine (Hirschsprung disease). {ECO:0000269|PubMed:18348274, ECO:0000269|PubMed:21898658, ECO:0000269|PubMed:9462749}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome and Hirschsprung disease (PCWH) [MIM:609136]: A complex neurocristopathy that includes features of 4 distinct syndromes: peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome and Hirschsprung disease. {ECO:0000269|PubMed:10762540, ECO:0000269|PubMed:15004559, ECO:0000269|PubMed:19208381, ECO:0000269|PubMed:21898658}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.451

Intolerance Scores

RVIS EVS
-0.47
RVIS percentile EVS
23.04

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.624

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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