GeneBe

TBX6

protein-coding

T-box transcription factor 6, the group of T-box transcription factors

Gene summary

This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. Knockout studies in mice indicate that this gene is important for specification of paraxial mesoderm structures. [provided by RefSeq, Aug 2008]

MANE transcript

NM_004608.4

Inheritance

SD, AD, AR

ClinVar variants

P:29U:183B:74

Top phenotype

Spondylocostal dysostosis 5

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr16:30,085,793-30,091,924

External References & Databases

Ensembl (ENSG00000149922)NCBI Gene (6911)OMIM (602427)HGNC:11605GenCCUniProt (O95947)AlphaFoldClinVar (TBX6)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~6.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spondylocostal dysostosis 5MODERATE

Inheritance Pattern: SD

Disease ID:MONDO:0007389

Submitter: Ambry Genetics

congenital anomaly of kidney and urinary tractLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019719

Submitter: Ambry Genetics

autosomal dominant spondylocostal dysostosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015826

Submitter: Orphanet

Mayer-Rokitansky-Kuster-Hauser syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0017771

Submitter: PanelApp Australia

spondylocostal dysostosis 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007389

Submitter: PanelApp Australia

spondylocostal dysostosis 5LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0007389

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Spondylocostal dysostosis 5AD/AR

Manifestation: Musculoskeletal

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: 23335591; 25564734; 28054739; 31015262Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TBX6 variants in ClinVar

8 Conditions Cataloged
not providedTotal: 258
Inborn genetic diseasesTotal: 60
Spondylocostal dysostosis 5Total: 32
ScoliosisTotal: 13
TBX6-related disorderTotal: 12
Neurodevelopmental abnormalityTotal: 3
not specifiedTotal: 2
Spondylocostal dysostosis 2, autosomal recessiveTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004608.4. 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
6
clinvar
65
clinvar
5
clinvar
 76
missense
1
clinvar
5
clinvar
166
clinvar
3
clinvar
1
clinvar
 176
nonsense
2
clinvar
1
clinvar
2
clinvar
 5
start loss
1
clinvar
 1
frameshift
8
clinvar
10
clinvar
5
clinvar
 23
splice donor/acceptor (+/-2bp)
2
clinvar
3
clinvar
 5
Total1118183686286

Highest pathogenic variant AF is 0.000104704646

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_004608.4RefSeqNP_004599.28MANE Select
ENST00000395224.7EnsemblENSP00000378650.28MANE Select
ENST00000279386.6EnsemblENSP00000279386.28Standard
ENST00000279386.7EnsemblENSP00000279386.28Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
tbx6Danio rerio

Structure: CaP motoneuron

Quality: decreased length

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Neural Crest Differentiation
  • Gene regulatory network modelling somitogenesis
  • Mesodermal Commitment Pathway

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • mesoderm formation
  • cell fate specification
  • mesoderm development
  • anatomical structure morphogenesis

Molecular Function

  • RNA polymerase II distal enhancer sequence-specific DNA binding
  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • RNA polymerase II transcription factor binding
  • RNA polymerase II activating transcription factor binding
  • DNA binding

Cellular Component

  • nuclear chromatin

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000395224
Coding exons
8
Length
6095
Individuals with no LoFs
125685
Homozygous LoFs
0
Heterozygous LoFs
63
Defined
125748
p
0.000251
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.5352542790.9100.00001862745
Missense (PolyPhen)87122.590.709671208
Synonymous0.1651131150.9800.00000764955
Loss of Function2.57719.10.3660.00000115192

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.000240.00023rare
Ashkenazi Jewish0.00170.0017notable
East Asian0.000170.00016rare
Finnish0.000690.00069rare
European (Non-Finnish)0.000140.00012rare
South Asian0.000160.00016rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: T-box transcription factor that plays an essential role in the determination of the fate of axial stem cells: neural vs mesodermal. Acts in part by down-regulating, a specific enhancer (N1) of SOX2, to inhibit neural development. Seems to play also an essential role in left/right axis determination and acts through effects on Notch signaling around the node as well as through an effect on the morphology and motility of the nodal cilia (By similarity). {ECO:0000250}.;
Disease
DISEASE: Spondylocostal dysostosis 5 (SCDO5) [MIM:122600]: A rare condition of variable severity characterized by vertebral and costal anomalies. The main feature include dwarfism, vertebral fusion, hemivertebrae, posterior rib fusion, reduced rib number, and other rib malformations. SCDO5 inheritance can be autosomal dominant or recessive. {ECO:0000269|PubMed:23335591, ECO:0000269|PubMed:25564734}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.120

Intolerance Scores

LoFtool
0.220
RVIS EVS
-0.05
RVIS percentile EVS
50.22

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Indispensability pred.
N
Indispensability score
0.381

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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