TBR1

protein-coding

T-box brain transcription factor 1, the group of T-box transcription factors

Gene summary

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]

MANE transcript

NM_006593.4

Inheritance

AR, AD

ClinVar variants

P:78U:194B:50

Top phenotype

Intellectual developmental disorder with autism and speech delay

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr2:161,416,297-161,425,870

External References & Databases

Ensembl (ENSG00000136535)

Transcript & Mutation Effects

hg38 • Region Span ~9.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

occipital pachygyria and polymicrogyriaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013583

Submitter: Orphanet

autismDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0005260

Submitter: G2P

intellectual developmental disorder with autism and speech delaySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011627

Submitter: PanelApp Australia

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

Variation in TBR1 was first reported in individuals in relation to autism spectrum disorder in 2014 by Deriziotis et al. (PMID: 25232744). TBR1 has also been associated with intellectual developmental disorder with autism and speech delay (OMIM #606053), 2q24 microdeletion syndrome, occipital pachygyria and polymicrogyria. Since then, phenotypes associated with variants in TBR1 have been expanded and range from autism spectrum disorder, delayed speech and language development, joint hypermobility, severe intellectual disability/global developmental delay, abnormality of the skull, cerebral palsy, etc. (Deriziotis et al., 2014 PMID: 25232744; Huang et al., 2014 PMID: 24441682; Palumbo et al., 2014 PMID:24458984).Per criteria outlined by the ClinGen Lumping and Splitting Working Group, the ID/Autism GCEP decided to lump into one disease entity, complex neurodevelopmental disorder (Mondo:0100038). There are individuals that have been reported with other phenotypes including joint hypermobility and muscle dysfunction. It is unclear at this time whether these phenotypes are related to variants in TBR1 or are due to other circumstances. Most proband information was collected from large case control studies where other phenotypic features are not reported, therefore making the phenotypic profile unclear. Twenty-six variants (missense, in-frame indel, frameshift) have been included in this curation. These variants have been reported in thirty-two individuals across two publications (PMIDs: 25232744, 32005960).More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity appears to be LOF. This gene-disease relationship is also supported by protein interactions, expression studies, animal models, and biochemical function studies (PMIDs: 25232744, 24309898, 10749215, 32005960). In summary, TBR1 is definitively associated with autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This curation was approved by the ID/Autism Gene Curation Expert Panel on 03/25/2020.

Clinical Genomic Database (CGD)

Intellectual developmental disorder with autism and speech delayAD

Manifestation: Neurologic

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: 25232744; 29288087; 30250039; 30268909

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TBR1 variants in ClinVar

34 Conditions Cataloged

not providedTotal: 151

Inborn genetic diseasesTotal: 106

Intellectual developmental disorder with autism and speech delayTotal: 75

Autistic behaviorTotal: 15

TBR1-related disorderTotal: 12

Moderate global developmental delayTotal: 12

Severe global developmental delayTotal: 8

Intellectual disabilityTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006593.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	29 clinvar	3 clinvar	33
missense	7 clinvar	18 clinvar	190 clinvar	18 clinvar		233
nonsense	4 clinvar	11 clinvar	2 clinvar			17
start loss						0
frameshift	14 clinvar	19 clinvar	1 clinvar			34
splice donor/acceptor (+/-2bp)	3 clinvar	2 clinvar				5
Total	28	50	194	47	3	322

Highest pathogenic variant AF is 0.0000015110169

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006593.4	RefSeq	NP_006584.1	6	MANE Select
ENST00000389554.8	Ensembl	ENSP00000374205.3	6	MANE Select
ENST00000410035.1	Ensembl	ENSP00000387023.1	4	Standard
ENST00000410035.2	Ensembl	ENSP00000387023.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

conditioned taste aversion
brain development
specification of animal organ identity
amygdala development
commitment of neuronal cell to specific neuron type in forebrain

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription factor activity
protein binding
protein kinase binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000389554
Coding exons: 6
Length: 9777
Individuals with no LoFs: 125456
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125457
p: 0.00000399

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.64	172	368	0.467	0.0000169	4420
Missense (PolyPhen)		66	167.09	0.39499		1943
Synonymous	0.687	145	156	0.930	0.00000745	1373
Loss of Function	4.39	1	24.4	0.0409	0.00000112	268

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable transcriptional regulator involved in developmental processes. Required for normal brain development.;

Recessive Scores

pRec: 0.380

Intolerance Scores

RVIS EVS: -0.41
RVIS percentile EVS: 26.23

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.980

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium