TBX6

Summary

TBX6 (T-box transcription factor 6, HGNC:11605) is a protein-coding gene on chromosome 16p11.2, encoding T-box transcription factor TBX6 (O95947). T-box transcription factor that plays an essential role in the determination of the fate of axial stem cells: neural vs mesodermal.

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.

Source: NCBI Gene 6911 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Mayer-Rokitansky-Kuster-Hauser syndrome (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 25
• Clinical variants (ClinVar): 335 total — 14 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 57
• Transcription factor: yes — 13 downstream targets (CollecTRI)
• MANE Select transcript: NM_004608

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11605
Approved symbol	TBX6
Name	T-box transcription factor 6
Location	16p11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000149922
Ensembl biotype	protein_coding
OMIM	602427
Entrez	6911

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 nonsense_mediated_decay

ENST00000279386, ENST00000395224, ENST00000553607, ENST00000567664, ENST00000900317, ENST00000900318, ENST00000931584, ENST00000931585

RefSeq mRNA: 1 — MANE Select: NM_004608 NM_004608

CCDS: CCDS10670

Canonical transcript exons

ENST00000395224 — 9 exons

Exon	Start	End
ENSE00000678805	30090758	30090992
ENSE00000992970	30088545	30088615
ENSE00000992973	30086778	30086851
ENSE00000992975	30088943	30089210
ENSE00000992978	30088693	30088839
ENSE00001167391	30085793	30086438
ENSE00001520987	30091076	30091241
ENSE00001601125	30091873	30091924
ENSE00003632150	30086512	30086695

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 91.62.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4050 / max 44.7776, expressed in 121 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157013	0.2849	62
157015	0.0651	27
157014	0.0549	23

Top tissues by expression

282 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	91.62	gold quality
buccal mucosa cell	CL:0002336	85.62	gold quality
diaphragm	UBERON:0001103	80.67	gold quality
esophagus mucosa	UBERON:0002469	79.99	gold quality
triceps brachii	UBERON:0001509	76.57	gold quality
gluteal muscle	UBERON:0002000	76.43	gold quality
pancreatic ductal cell	CL:0002079	75.60	silver quality
quadriceps femoris	UBERON:0001377	72.99	gold quality
Brodmann (1909) area 10	UBERON:0013541	72.93	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	72.88	gold quality
esophagus	UBERON:0001043	72.68	gold quality
vastus lateralis	UBERON:0001379	72.64	gold quality
vagina	UBERON:0000996	71.79	gold quality
deltoid	UBERON:0001476	71.59	silver quality
secondary oocyte	CL:0000655	71.39	gold quality
tibialis anterior	UBERON:0001385	71.04	silver quality
endometrium epithelium	UBERON:0004811	71.03	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	70.05	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	69.87	gold quality
cerebellar vermis	UBERON:0004720	69.69	gold quality
ileal mucosa	UBERON:0000331	69.35	gold quality
body of pancreas	UBERON:0001150	69.26	gold quality
skeletal muscle tissue	UBERON:0001134	69.13	gold quality
granulocyte	CL:0000094	68.90	gold quality
skin of abdomen	UBERON:0001416	68.65	gold quality
muscle tissue	UBERON:0002385	68.55	gold quality
lateral nuclear group of thalamus	UBERON:0002736	67.58	gold quality
biceps brachii	UBERON:0001507	67.44	gold quality
skin of leg	UBERON:0001511	67.23	gold quality
ectocervix	UBERON:0012249	67.11	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	58.90
E-ANND-3	yes	3.06

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

13 targets.

Target	Regulation
CD44
CDH17
CDKN1B
CYP21A1P
DCSTAMP
DLL1	Unknown
FGF8	Activation
HES7	Activation
MESP2	Activation
MSGN1
SERPINB5
TBX6
WNT3A

JASPAR motifs

Motif	Name	Family
MA1567.1	TBX6	TBX6-related factors

JASPAR matrix evidence (PMIDs): PMID:12093383

Upstream regulators (CollecTRI, top): GATA4, NKX2-5, PITX2, RBPJ, SMAD4, SMAD6, TBX18, TBX5, TBX6, TBXT

miRNA regulators (miRDB)

55 targeting TBX6, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-4761-5P	99.51	66.69	804
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-4786-3P	99.36	68.35	1390

Literature-anchored findings (GeneRIF, showing 21)

• Tbx18 interacts with Gata4 and Nkx2-5 and competes Tbx5-mediated activation of the cardiac Natriuretic peptide precursor type a-promoter. Tbx18 down-regulates Tbx6-activated Delta-like 1 expression in the somitic mesoderm in vivo (PMID:17584735)
• first report on single nucleotide polymorphisms of TBX6 gene in congenital scoliosis (CS) that suggests genetic variants of TBX6 gene is associated with CS in the Chinese Han population. (PMID:20228709)
• we have used exome capture and next-generation sequencing to identify a stoploss mutation in TBX6 that segregates with disease in two generations of one family. (PMID:23335591)
• Data have identified TBX6 as a new gene associated with Mullerian aplasia. The results also support the relevance of LHX1 and CNVs in the development of this congenital malformation. (PMID:23954021)
• Compound inheritance of a rare null mutation and a hypomorphic allele of TBX6 accounted for up to 11% of congenital scoliosis cases in the series that we analyzed. (PMID:25564734)
• Mutations of RBM8A and TBX6 are associated with disorders of the mullerian ducts. (PMID:25813282)
• TBX6 plays a role during human spine development and interacts with other key elements during the process of somitogenesis [review] (PMID:27437870)
• One patient with extensive SDV was carrying a proximal 16p11.2 microdeletion associated with a TBX6 rare missense change. One patient with a clinical diagnosis of SCD was compound heterozygous for two TBX6 rare missense changes. The three rare variants were affecting the chromatin-binding domain. Our data illustrate the variable expressivity of recessive TBX6 ranging from congenital scoliosis to spondylocostal dysostos. (PMID:27861764)
• Although all Chinese patients had one or more hemivertebrae, two Japanese patients did not have hemivertebra. The compound heterozygosity of null mutations and the common risk haplotype in TBX6 also causes CS in Japanese patients with similar incidence. Hemivertebra was not a specific type of spinal malformation in TBX6-associated CS (TACS). (PMID:28054739)
• this study is the first proteomic research to delineate the total and differential serum proteins in TBX6 haploinsufficiency-caused Congenital scoliosis. (PMID:28944995)
• our findings in the newly collected human Congenital vertebral malformations (CVMs) subjects and Tbx6 mouse models consistently support the contention that TBX6 compound inheritance causes CVMs, potentially via a gene dosage-dependent mechanism. (PMID:30307510)
• In this work, we identified a novel splicing variant of TBX6 in human CAKUT. Our experimental observations suggested that the TBX6 noncoding variant can affect gene expression and may potentially be involved in human CAKUT. (PMID:30604070)
• The type and distribution of vertebral column abnormalities in TBX6/Tbx6 compound inheritance implicate subtle perturbations in gene dosage as a cause of spine developmental birth defects responsible for about 10% of congenital scoliosis (PMID:30636772)
• association of variants in TBX6 with malformations of the mullerian ducts, is reported. (PMID:30739119)
• Our study suggests that bi-allelic loss of function variants of TBX6 cause a spectrum of phenotypes including CS and SCD, depending on the severity of the loss of TBX6 function. (PMID:31015262)
• TBX6 missense variants expand the mutational spectrum in a non-Mendelian inheritance disease. (PMID:31471994)
• Increased TBX6 gene dosages induce congenital cervical vertebral malformations in humans and mice. (PMID:31888956)
• Genetic variants of TBX6 and TBXT identified in patients with congenital scoliosis in Southern China. (PMID:32672867)
• An additional piece in the TBX6 gene dosage model: A novel nonsense variant in a fetus with severe spondylocostal dysostosis. (PMID:33058178)
• Functional characteristics of a broad spectrum of TBX6 variants in Mayer-Rokitansky-Kuster-Hauser syndrome. (PMID:36112137)
• TBX6 as a cause of a combined skeletal-kidney dysplasia syndrome. (PMID:36161696)

Cross-species orthologs

17 orthologs

Organism	Symbol	Gene ID
danio_rerio	tbx6	ENSDARG00000011785
mus_musculus	Tbx6	ENSMUSG00000030699
rattus_norvegicus	Tbx6	ENSRNOG00000019771
drosophila_melanogaster	H15	FBGN0016660
drosophila_melanogaster	Doc1	FBGN0028789
drosophila_melanogaster	Doc3	FBGN0035954
drosophila_melanogaster	Doc2	FBGN0035956
drosophila_melanogaster	mid	FBGN0261963
drosophila_melanogaster	ocm	FBGN0266083
caenorhabditis_elegans		WBGENE00003106
caenorhabditis_elegans		WBGENE00004750
caenorhabditis_elegans		WBGENE00006545
caenorhabditis_elegans		WBGENE00006546
caenorhabditis_elegans		WBGENE00006556
caenorhabditis_elegans		WBGENE00006557
caenorhabditis_elegans		WBGENE00006559
caenorhabditis_elegans		WBGENE00044798

Paralogs (16): TBX21 (ENSG00000073861), TBX5 (ENSG00000089225), TBX15 (ENSG00000092607), TBX18 (ENSG00000112837), TBX2 (ENSG00000121068), TBX4 (ENSG00000121075), TBX22 (ENSG00000122145), TBX3 (ENSG00000135111), TBR1 (ENSG00000136535), TBX19 (ENSG00000143178), EOMES (ENSG00000163508), TBXT (ENSG00000164458), TBX20 (ENSG00000164532), TBX10 (ENSG00000167800), MGA (ENSG00000174197), TBX1 (ENSG00000184058)

Protein

Protein identifiers

T-box transcription factor TBX6 — O95947 (reviewed: O95947)

All UniProt accessions (1): O95947

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. Forms a dimeric complex with DNA (in vitro).

Subcellular location. Nucleus.

Tissue specificity. Expressed in fetal tail bud, posterior spinal tissue, intervertebral disk and testis. Also expressed in adult testis, kidney, lung, muscle and thymus.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
O95947-1	1	yes
O95947-2	2

RefSeq proteins (1): NP_004599* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001699	TF_T-box	Family
IPR002070	TF_Brachyury	Family
IPR008967	p53-like_TF_DNA-bd_sf	Homologous_superfamily
IPR018186	TF_T-box_CS	Conserved_site
IPR036960	T-box_sf	Homologous_superfamily
IPR046360	T-box_DNA-bd	Domain

Pfam: PF00907

UniProt features (16 total): sequence variant 6, sequence conflict 2, region of interest 2, compositionally biased region 2, splice variant 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95947-F1	66.18	0.39

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-9793380	Formation of paraxial mesoderm
R-HSA-9824272	Somitogenesis
R-HSA-9832991	Formation of the posterior neural plate
R-HSA-1266738	Developmental Biology
R-HSA-9758941	Gastrulation

MSigDB gene sets: 377 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, E2F_Q4, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_CELL_MATURATION, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_AXIS_SPECIFICATION, E2F4DP1_01, GOBP_EMBRYONIC_AXIS_SPECIFICATION, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, GOBP_NEURON_MATURATION, AACYNNNNTTCCS_UNKNOWN, GOBP_NEUROGENESIS

GO Biological Process (14): negative regulation of transcription by RNA polymerase II (GO:0000122), cell fate specification (GO:0001708), regulation of transcription by RNA polymerase II (GO:0006357), mesoderm development (GO:0007498), mesodermal cell fate specification (GO:0007501), anatomical structure morphogenesis (GO:0009653), negative regulation of neuron projection development (GO:0010977), negative regulation of neuron maturation (GO:0014043), signal transduction involved in regulation of gene expression (GO:0023019), somite rostral/caudal axis specification (GO:0032525), positive regulation of transcription by RNA polymerase II (GO:0045944), mesoderm formation (GO:0001707), regulation of DNA-templated transcription (GO:0006355), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA binding (GO:0003677), transcription corepressor activity (GO:0003714), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), sequence-specific double-stranded DNA binding (GO:1990837), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Gastrulation	2
Formation of paraxial mesoderm	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
regulation of DNA-templated transcription	3
negative regulation of DNA-templated transcription	2
regulation of gene expression	2
DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cell fate commitment	1
cellular developmental process	1
tissue development	1
cell fate specification	1
mesodermal cell fate commitment	1
developmental process	1
anatomical structure development	1
regulation of neuron projection development	1
neuron projection development	1
negative regulation of cell projection organization	1
regulation of neuron maturation	1
neuron maturation	1
negative regulation of cell maturation	1
signal transduction	1
embryonic axis specification	1
somitogenesis	1
anterior/posterior axis specification	1
positive regulation of DNA-templated transcription	1
formation of primary germ layer	1
mesoderm morphogenesis	1
regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
nucleic acid binding	1
transcription coregulator activity	1
DNA-binding transcription factor binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
binding	1

Protein interactions and networks

STRING

1258 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TBX6	MESP2	Q0VG99	917
TBX6	MEOX1	P50221	767
TBX6	RIPPLY2	Q5TAB7	750
TBX6	LFNG	Q8NES3	744
TBX6	MSGN1	A6NI15	735
TBX6	FGF8	P55075	729
TBX6	PAX3	P23760	711
TBX6	BMP4	P12644	705
TBX6	DLL1	O00548	686
TBX6	NKX2-5	P52952	682
TBX6	HOXC10	Q9NYD6	678
TBX6	TAOK2	Q9UL54	639
TBX6	MIXL1	Q9H2W2	628
TBX6	RIPPLY1	Q0D2K3	615
TBX6	ZIC1	Q15915	612

IntAct

122 interactions, top by confidence:

A	B	Type	Score
TBX6	TOX4	psi-mi:“MI:0915”(physical association)	0.780
TBX6	HSFY1	psi-mi:“MI:0915”(physical association)	0.780
HSFY1	TBX6	psi-mi:“MI:0915”(physical association)	0.780
TOX4	TBX6	psi-mi:“MI:0915”(physical association)	0.780
C1orf94	TBX6	psi-mi:“MI:0915”(physical association)	0.670
TBX6	C1orf94	psi-mi:“MI:0915”(physical association)	0.670
TBX6	RBPMS	psi-mi:“MI:0915”(physical association)	0.670
RBPMS	TBX6	psi-mi:“MI:0915”(physical association)	0.560
TBX6	RBPMS	psi-mi:“MI:0915”(physical association)	0.560
TBX19	TBX6	psi-mi:“MI:0915”(physical association)	0.560
TBX6	POU6F2	psi-mi:“MI:0915”(physical association)	0.560
CRX	TBX6	psi-mi:“MI:0915”(physical association)	0.560
	TBX6	psi-mi:“MI:0915”(physical association)	0.560
TBX6	USP54	psi-mi:“MI:0915”(physical association)	0.560
TBX6	PRR20D	psi-mi:“MI:0915”(physical association)	0.560
KRTAP6-3	TBX6	psi-mi:“MI:0915”(physical association)	0.560
TBX6	TLE5	psi-mi:“MI:0915”(physical association)	0.560
TBX6	TCP11L1	psi-mi:“MI:0915”(physical association)	0.560
TBX6	MAGED1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (46): TOX4 (Two-hybrid), RBPMS (Two-hybrid), C1orf94 (Two-hybrid), HSFY1 (Two-hybrid), TBX6 (Two-hybrid), TBX6 (Two-hybrid), TBX6 (Two-hybrid), TBX6 (Two-hybrid), TBX6 (Two-hybrid), TBX6 (Two-hybrid), TBX6 (Two-hybrid), TBX6 (Two-hybrid), TBX6 (Two-hybrid), TBX6 (Two-hybrid), TBX6 (Two-hybrid)

ESM2 similar proteins: A1YF56, A2AEV7, A6NCS4, A7Y7W2, D3ZJK7, E1BEA8, F1MUS9, O15534, O35973, O43435, O43638, O60248, O75333, O77728, O94983, O95935, O95947, P22736, P46099, P51666, P56261, P57082, P70325, P70327, Q03484, Q0V8F0, Q15744, Q497V6, Q5DTT2, Q61660, Q61663, Q63HR2, Q64731, Q66JL1, Q6PZD9, Q6ZQN5, Q80Y50, Q810F8, Q861Q9, Q8AV66

Diamond homologs: A1YF56, A2AWL7, D3ZJK7, E1BEA8, O01409, O13161, O15119, O15178, O17212, O43435, O54839, O60806, O70306, O73718, O75333, O95935, O95936, O95947, P20293, P24781, P55965, P56158, P57082, P70323, P70324, P70325, P70326, P70327, P79742, P79777, P79778, P79779, P79944, P80492, P87377, P90971, Q07998, Q13207, Q16650, Q17134

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SMURF1	“down-regulates quantity by destabilization”	TBX6	polyubiquitination
SMAD6	“down-regulates quantity by destabilization”	TBX6	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

335 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	9
Uncertain significance	185
Likely benign	89
Benign	11

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
100633	NM_004608.4(TBX6):c.1311A>T (p.Ter437Cys)	Pathogenic
1323679	NM_004608.4(TBX6):c.1143dup (p.Tyr382fs)	Pathogenic
188054	NM_004608.4(TBX6):c.1250dup (p.Leu419fs)	Pathogenic
188055	NM_004608.4(TBX6):c.266dup (p.Val91fs)	Pathogenic
2221167	NM_004608.4(TBX6):c.699G>A (p.Trp233Ter)	Pathogenic
243053	NM_004608.4(TBX6):c.704dup (p.Met236fs)	Pathogenic
243054	NM_004608.4(TBX6):c.1169dup (p.His391fs)	Pathogenic
252362	NM_004608.4(TBX6):c.1179_1180del (p.Gly395fs)	Pathogenic
3339290	NM_004608.4(TBX6):c.990del (p.Glu332fs)	Pathogenic
599077	NM_004608.4(TBX6):c.221dup (p.Thr75fs)	Pathogenic
638096	GRCh37/hg19 16p11.2(chr16:29595483-30198151)x1	Pathogenic
694406	NM_004608.4(TBX6):c.473_475dup (p.Trp158_Glu159insGly)	Pathogenic
694414	NM_004608.4(TBX6):c.418C>T (p.Leu140Phe)	Pathogenic
827682	NM_004608.4(TBX6):c.1148C>A (p.Ser383Ter)	Pathogenic
1325177	NM_004608.4(TBX6):c.914-2A>C	Likely pathogenic
2576015	NM_004608.4(TBX6):c.1112dup (p.Glu372fs)	Likely pathogenic
2628423	NM_004608.4(TBX6):c.834dup (p.Lys279Ter)	Likely pathogenic
2633386	NM_004608.4(TBX6):c.370del (p.Cys124fs)	Likely pathogenic
3027069	NM_004608.4(TBX6):c.117del (p.Glu40fs)	Likely pathogenic
3032399	NM_004608.4(TBX6):c.1083del (p.His362fs)	Likely pathogenic
3062294	NM_004608.4(TBX6):c.1309T>C (p.Ter437Arg)	Likely pathogenic
3383213	NM_004608.4(TBX6):c.989_990dup (p.Gly331fs)	Likely pathogenic
694404	NM_004608.4(TBX6):c.424G>T (p.Asp142Tyr)	Likely pathogenic

SpliceAI

1066 predictions. Top by Δscore:

Variant	Effect	Δscore
16:30086507:CTCA:C	donor_loss	1.0000
16:30086508:TCA:T	donor_loss	1.0000
16:30086509:CACCT:C	donor_loss	1.0000
16:30086510:A:AT	donor_loss	1.0000
16:30086691:TGTGT:T	acceptor_gain	1.0000
16:30086692:GTGT:G	acceptor_gain	1.0000
16:30086693:TGT:T	acceptor_gain	1.0000
16:30086694:GT:G	acceptor_gain	1.0000
16:30086696:C:CC	acceptor_gain	1.0000
16:30086773:CTCA:C	donor_loss	1.0000
16:30086774:TCA:T	donor_loss	1.0000
16:30086775:CA:C	donor_loss	1.0000
16:30086776:A:AC	donor_gain	1.0000
16:30086776:ACCT:A	donor_gain	1.0000
16:30086777:C:CC	donor_gain	1.0000
16:30086777:C:CT	donor_loss	1.0000
16:30086777:CCT:C	donor_gain	1.0000
16:30086777:CCTC:C	donor_gain	1.0000
16:30086849:TCCC:T	acceptor_loss	1.0000
16:30086850:CC:C	acceptor_gain	1.0000
16:30086851:CC:C	acceptor_gain	1.0000
16:30086851:CCTGG:C	acceptor_loss	1.0000
16:30086852:C:CC	acceptor_gain	1.0000
16:30086852:CTGGG:C	acceptor_loss	1.0000
16:30086853:T:G	acceptor_loss	1.0000
16:30088688:CTCA:C	donor_loss	1.0000
16:30088689:TCA:T	donor_loss	1.0000
16:30088690:CA:C	donor_loss	1.0000
16:30088691:A:AC	donor_gain	1.0000
16:30088691:A:AT	donor_loss	1.0000

AlphaMissense

2789 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:30088571:G:C	F271L	1.000
16:30088571:G:T	F271L	1.000
16:30088572:A:C	F271C	1.000
16:30088572:A:G	F271S	1.000
16:30088573:A:G	F271L	1.000
16:30088577:T:A	K269N	1.000
16:30088577:T:G	K269N	1.000
16:30088581:G:T	A268D	1.000
16:30088583:A:C	F267L	1.000
16:30088583:A:T	F267L	1.000
16:30088584:A:C	F267C	1.000
16:30088585:A:G	F267L	1.000
16:30088585:A:T	F267I	1.000
16:30088589:A:C	N265K	1.000
16:30088589:A:T	N265K	1.000
16:30088591:T:C	N265D	1.000
16:30088599:A:C	I262S	1.000
16:30088599:A:G	I262T	1.000
16:30088599:A:T	I262N	1.000
16:30088601:C:A	K261N	1.000
16:30088601:C:G	K261N	1.000
16:30088603:T:C	K261E	1.000
16:30088706:T:C	Y252C	1.000
16:30088707:A:G	Y252H	1.000
16:30088723:G:C	F246L	1.000
16:30088723:G:T	F246L	1.000
16:30088724:A:G	F246S	1.000
16:30088725:A:G	F246L	1.000
16:30088967:G:C	N199K	1.000
16:30088967:G:T	N199K	1.000

dbSNP variants (sampled 300 via entrez): RS1000185115 (16:30087620 G>A,C), RS1000305364 (16:30093887 C>A,T), RS1000409483 (16:30088196 C>T), RS1002342627 (16:30090191 A>T), RS1002804925 (16:30090501 C>T), RS1002806697 (16:30093430 T>A), RS1002889944 (16:30093003 C>T), RS1003173890 (16:30086061 AG>A,AGG), RS1003262647 (16:30089792 T>C), RS1003402098 (16:30092011 G>T), RS1003959607 (16:30091315 G>A), RS1004827037 (16:30090630 T>C), RS1004912619 (16:30092273 C>T), RS1004965002 (16:30092562 G>A), RS1005998252 (16:30085470 G>A,C)

Disease associations

OMIM: gene MIM:602427 | disease phenotypes: MIM:122600, MIM:608681

GenCC curated gene-disease

Disease	Classification	Inheritance
spondylocostal dysostosis 5	Strong	Autosomal recessive
Mayer-Rokitansky-Kuster-Hauser syndrome	Strong	Autosomal recessive
autosomal dominant spondylocostal dysostosis	Supportive	Autosomal dominant
congenital anomaly of kidney and urinary tract	Limited	Autosomal dominant

Mondo (6): spondylocostal dysostosis 5 (MONDO:0007389), spondylocostal dysostosis 2, autosomal recessive (MONDO:0012097), scoliosis (MONDO:0005392), congenital anomaly of kidney and urinary tract (MONDO:0019719), autosomal dominant spondylocostal dysostosis (MONDO:0015826), Mayer-Rokitansky-Kuster-Hauser syndrome (MONDO:0017771)

Orphanet (1): Autosomal recessive spondylocostal dysostosis (Orphanet:2311)

HPO phenotypes

57 total (30 of 57 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000069	Abnormality of the ureter
HP:0000175	Cleft palate
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000269	Prominent occiput
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000358	Posteriorly rotated ears
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000582	Upslanted palpebral fissure
HP:0000768	Pectus carinatum
HP:0000772	Abnormal rib morphology
HP:0000776	Congenital diaphragmatic hernia
HP:0000902	Rib fusion
HP:0000913	Posterior rib fusion
HP:0000921	Missing ribs
HP:0001249	Intellectual disability
HP:0001511	Intrauterine growth retardation
HP:0001537	Umbilical hernia
HP:0002093	Respiratory insufficiency
HP:0002205	Recurrent respiratory infections
HP:0002435	Meningocele

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST002539_82	Schizophrenia	5.000000e-11
GCST002541_107	Menarche (age at onset)	2.000000e-09
GCST004521_236	Autism spectrum disorder or schizophrenia	4.000000e-10
GCST004601_137	Red blood cell count	3.000000e-27
GCST004602_227	Mean corpuscular volume	5.000000e-32
GCST004606_91	Eosinophil count	1.000000e-17
GCST004624_167	Sum eosinophil basophil counts	8.000000e-15
GCST004630_175	Mean corpuscular hemoglobin	5.000000e-33
GCST005996_3	Red blood cell count	5.000000e-13
GCST006803_23	Schizophrenia	6.000000e-13
GCST007293_15	Body fat distribution (arm fat ratio)	6.000000e-06
GCST007293_81	Body fat distribution (arm fat ratio)	4.000000e-08
GCST009597_27	Multiple sclerosis	1.000000e-21
GCST010703_269	Brain morphology (MOSTest)	4.000000e-13
GCST90002381_84	Eosinophil count	1.000000e-47
GCST90002383_239	Hematocrit	3.000000e-29
GCST90002384_358	Hemoglobin	1.000000e-22
GCST90002385_77	High light scatter reticulocyte count	1.000000e-11
GCST90002390_82	Mean corpuscular hemoglobin	1.000000e-69
GCST90002392_499	Mean corpuscular volume	1.000000e-72
GCST90002395_192	Mean platelet volume	3.000000e-11
GCST90002396_584	Mean reticulocyte volume	5.000000e-63
GCST90002397_236	Mean spheric corpuscular volume	5.000000e-67
GCST90002403_672	Red blood cell count	6.000000e-91
GCST90002405_307	Reticulocyte count	4.000000e-18

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0004305	erythrocyte count
EFO:0004842	eosinophil count
EFO:0005090	basophil count
EFO:0004527	mean corpuscular hemoglobin
EFO:0004341	body fat distribution
EFO:0004346	neuroimaging measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0007986	reticulocyte count
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D012600	Scoliosis	C05.116.900.800.875
C566906	Cakut (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tretinoin	affects expression, decreases reaction, increases expression, increases reaction, decreases expression	3
Chir 99021	increases expression, increases reaction, affects cotreatment, decreases expression, decreases reaction	2
pirinixic acid	affects binding, decreases expression, increases activity	1
N(4)-hydroxycytidine	decreases expression	1
butyraldehyde	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
2,4-di-tert-butylphenol	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, increases reaction, decreases reaction	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	decreases response to substance	1
Dolutegravir	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation	1
Dexamethasone	affects expression	1
Estradiol	decreases expression	1
Folic Acid	decreases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression	1
Niclosamide	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	decreases expression	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	decreases expression	1
Lactic Acid	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A8M2	SEES3-1V human TBX6, clone1	Embryonic stem cell	Male
CVCL_A8M3	SEES3-1V human TBX6, clone2	Embryonic stem cell	Male
CVCL_A8M4	SEES3-1V human TBX6, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

223 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00508066	PHASE4	COMPLETED	Continuous Local Infusion of Anesthetic at the Incisional Site for Scoliosis Surgery
NCT00510575	PHASE4	COMPLETED	Surgical Outcomes Using Variable Rod Diameters in the Treatment of Idiopathic Scoliosis
NCT00768313	PHASE4	WITHDRAWN	Phase IV Comparing Rods of Yield Strengths to Correct Adolescent Idiopathic Scoliosis.
NCT00880607	PHASE4	COMPLETED	Intrathecal Morphine Versus Epidural Extended Release Morphine for Pediatric Patients Undergoing Spinal Fusion
NCT00958581	PHASE4	COMPLETED	Tranexamic Acid (TXA) Versus Epsilon Aminocaproic Acid (EACA) Versus Placebo for Spine Surgery
NCT01852747	PHASE4	TERMINATED	Comparison of Actifuse ABX and Local Bone in Spinal Surgery
NCT02464813	PHASE4	COMPLETED	Effect of Pregabalin on Immediate Post-operative and Longterm Pain
NCT02465099	PHASE4	TERMINATED	Posterior Spinal Fusion With Two Energy Dissection Techniques
NCT06540885	PHASE4	RECRUITING	A Comparison Between Palonosetron Versus Granisetron as PONV Prophylaxis in Scoliotic Patients Undergoing Spine Surgery
NCT06616220	PHASE4	COMPLETED	Dexamethasone for ESPB in Pain Management After Pediatric Idiopathic Scoliosis Surgery
NCT06789016	PHASE4	COMPLETED	Dexmedetomidine for ESPB in Pain Management After Pediatric Idiopathic Scoliosis Surgery
NCT03277430	PHASE3	UNKNOWN	Uterus Transplantation From Live Donors and From Deceased Donors - Clinical Study
NCT00323752	PHASE3	COMPLETED	Recombinant Human Erythropoietin Compared to Autologous Pre-Donation Prior to Scoliosis Surgery in Children.
NCT00684112	PHASE3	COMPLETED	Analgesic Effects of Gabapentin After Scoliosis Surgery in Children
NCT00737997	PHASE3	COMPLETED	Effect of Early Morphine Administration on the Development of Acute Opioid Tolerance During Pediatric Scoliosis Surgery
NCT01103115	PHASE3	COMPLETED	Calcium + Vitamin D Supplementation for Low Bone Mass in Adolescent Idiopathic Scoliosis (AIS)
NCT01108211	PHASE3	COMPLETED	Improving Low Bone Mass With Vibration Therapy in Adolescent Idiopathic Scoliosis (AIS)
NCT01205256	PHASE3	COMPLETED	IRB-HSR# 14145 R,S Methadone: Analgesia and Pharmacokinetics in Adolescents Undergoing Scoliosis Correction
NCT02558010	PHASE3	COMPLETED	Perioperative Methadone Use to Decrease Opioid Requirement in Pediatric Spinal Fusion Patients
NCT03537612	PHASE3	TERMINATED	Sensorial and Physiological Mechanism-based Assessments of Perioperative Pain
NCT00273598	PHASE2	COMPLETED	Comparing Two Instrumentation Systems for the Treatment of Adolescent Scoliosis
NCT01148888	PHASE2	COMPLETED	The Effect of Magnesium Sulfate on Motor and Somatosensory Evoked Potentials in Children Undergoing Scoliosis Surgery
NCT04115345	PHASE1	COMPLETED	A Study of a Renal Autologous Cell Therapy (REACT) in Patients With Chronic Kidney Disease (CKD) From Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).
NCT05694169	PHASE1	TERMINATED	A Study of Participants With Chronic Kidney Disease Previously Treated With REACT
NCT00154505	PHASE1	COMPLETED	Effects of Lateral Trunk Support on Spinal Alignment in Spinal Cord Injured Persons
NCT00155545	PHASE1	COMPLETED	Influence of Leg Length Discrepancy on the Spinal Shape and Biomechanics in Functional and Idiopathic Scoliosis Patients
NCT00671931	PHASE1	COMPLETED	Susceptibility of Motor-Evoked Potentials to Varying Targeted Blood Levels of Dexmedetomidine
NCT01677650	PHASE1	WITHDRAWN	Pharmacogenomics of Methadone in Spine Fusion Surgery
NCT04537364	Not specified	COMPLETED	Prediction of Renal Parenchymal Damage of CAKUT
NCT06921733	Not specified	RECRUITING	Ultrasound Localization Microscopy in Patient With Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)
NCT01911884	Not specified	COMPLETED	Assessment of Quality of Global and Sexual Life and Impact of Surgical and Non Surgical Vaginal Aplasia in Patients With a Rokitansky Syndrome
NCT02967822	Not specified	RECRUITING	Molecular Genetic Study of Mayer-Rokitansky-Kuster-Hauser Syndrome
NCT03252795	Not specified	RECRUITING	Uterus Transplantation From a Multi-organ Donor
NCT03307356	Not specified	ACTIVE_NOT_RECRUITING	The University of Pennsylvania Uterus Transplant for Uterine Factor Infertility Trial
NCT03689842	Not specified	RECRUITING	Feasibility Study of Uterine Transplantation From Living Donors in Terms of Efficacy and Safety in Patients With Mayer-Rokitansky-Küster-Hauser Syndrome (MRKH)
NCT04314869	Not specified	UNKNOWN	Uterus Transplantation Procedure From a Live Donor
NCT04923217	Not specified	COMPLETED	Quality of Life and Sexual Function in Vaginal Aplasia Patients After Davydov Procedure
NCT05263076	Not specified	RECRUITING	Uterine Transplant for Women With Absolute Uterine Factor Infertility (AUFI)
NCT05415540	Not specified	COMPLETED	Evolution of the Quality of Life and Experience of Young Women With Utero-vaginal Aplasia (MRKHPSY)
NCT05925361	Not specified	UNKNOWN	Peritoneum Vaginoplasty; Implementation According to IDEAL Framework