TBX6

Chr 16ADAR

T-box transcription factor 6

Also known as: SCDO5

NCBI Gene: 6911 ENSG00000149922 UniProt: O95947 OMIM: 602427

TBX6 encodes a T-box transcription factor that regulates axial stem cell fate determination between neural and mesodermal lineages and plays a role in left-right axis patterning during embryonic development. Mutations cause spondylocostal dysostosis 5, a vertebral segmentation disorder affecting the spine and ribs. Inheritance can be either autosomal dominant or autosomal recessive.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.691 OMIM phenotype

Clinical Summary— TBX6

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

25 unique Pathogenic / Likely Pathogenic· 185 VUS of 336 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TBX6

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.69LOEUF

pLI 0.007

Z-score 2.57

OE 0.37 (0.21–0.69)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.54Z-score

OE missense 0.91 (0.82–1.01)

254 obs / 279.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.21–0.69)

0≤0.351.4

Missense OE?0.91 (0.82–1.01)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 7 / 19.1Missense obs/exp: 254 / 279.2Syn Z: 0.17

This gene — mechanism propensity

0.6649th %ile

GOF

0.4776th %ile

LOF

0.50top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 84% of P/LP variants are LoF

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

LOFComparative analysis of serum proteome in congenital scoliosis patients with TBX6 haploinsufficiency - a first report pointing to lipid metabolism.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 28944995 ↗

ClinVar Variant Classifications

336 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14

Likely Pathogenic11

VUS185

Likely Benign94

Benign11

Conflicting15

Pathogenic

Likely Pathogenic

185

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	2	0	1	14
Likely Pathogenic	10	1	0	0	11
VUS	9	165	6	5	185
Likely Benign	0	2	30	62	94
Benign	0	1	5	5	11
Conflicting	—				15
Total	30	171	41	73	330

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

282 pathogenic / likely-pathogenic (of 302) ClinVar copy-number / structural variants overlap TBX6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →