TBR1

Chr 2AD

T-box brain transcription factor 1

Also known as: AUTS5, IDDAS, TBR-1, TES-56

NCBI Gene: 10716 ENSG00000136535 UniProt: Q16650 OMIM: 604616

TBR1 encodes a T-box transcription factor that regulates neuronal migration and axonal projection in the cerebral cortex, hippocampus, amygdala, and olfactory bulb. Loss-of-function mutations cause autosomal dominant intellectual developmental disorder with autism and speech delay. The gene is highly intolerant to loss-of-function variants, indicating haploinsufficiency as the mechanism of pathogenicity.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene is a member of a 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 numerous developmental processes. In mouse, the ortholog of this gene is expressed in the cerebral cortex, hippocampus, amygdala and olfactory bulb and is thought to play an important role in neuronal migration and axonal projection. In mouse, the C-terminal region of this protein was found to be necessary and sufficient for association with the guanylate kinase domain of calcium/calmodulin-dependent serine protein kinase. [provided by RefSeq, Dec 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.191 OMIM phenotype

Clinical Summary— TBR1

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

78 unique Pathogenic / Likely Pathogenic· 200 VUS of 337 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TBR1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.19LOEUF

pLI 0.999

Z-score 4.39

OE 0.04 (0.01–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.64Z-score

OE missense 0.47 (0.41–0.53)

172 obs / 368.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.19)

0≤0.351.4

Missense OE?0.47 (0.41–0.53)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 1 / 24.5Missense obs/exp: 172 / 368.4Syn Z: 0.69

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTBR1-related autismLOFAD

This gene — mechanism propensity

0.3196th %ile

GOF

0.2696th %ile

LOF

0.87top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 65% of P/LP variants are LoF · LOEUF 0.19 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

Literature Evidence

DNThe mutant protein retained the ability to homodimerize with wildtype TBR1 and to interact with CASK (300173), suggesting a dominant-negative effect, but was unable to interact with FOXP2 (605317).1

LOFThe identification of TBR1 as candidate for ID encourages further molecular studies to identify novel mutations to understand the pathogenic effects of its haploinsufficiency.2

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

References

ClinVar Variant Classifications

337 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27

Likely Pathogenic51

VUS200

Likely Benign44

Benign5

Conflicting6

Pathogenic

Likely Pathogenic

200

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	20	7	0	0	27
Likely Pathogenic	31	17	3	0	51
VUS	4	190	5	1	200
Likely Benign	0	13	2	29	44
Benign	0	1	1	3	5
Conflicting	—				6
Total	55	228	11	33	333

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

View in ClinVar →

24 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap TBR1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →