TCF20

protein-coding

transcription factor 20

Gene summary

This gene encodes a transcription factor that recognizes the platelet-derived growth factor-responsive element in the matrix metalloproteinase 3 promoter. The encoded protein is thought to be a transcriptional coactivator, enhancing the activity of transcription factors such as JUN and SP1. Mutations in this gene are associated with autism spectrum disorders. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

MANE transcript

NM_001378418.1

Inheritance

ClinVar variants

P:148U:609B:498

Top phenotype

Developmental delay with variable intellectual impairment and behavioral abnormalities

gnomAD constraint

pLI —, LoF o/e 0.03

Max pathogenic AF

—

Genomic locus

chr22:42,160,013-42,343,616

External References & Databases

Ensembl (ENSG00000100207)

Transcript & Mutation Effects

hg38 • Region Span ~183.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental delay with variable intellectual impairment and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032745

Submitter: Labcorp Genetics (formerly Invitae)

developmental delay with variable intellectual impairment and behavioral abnormalitiesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0032745

Submitter: ClinGen

The TCF20 gene is located on chromosome 22 at 22q13.2 and encodes the transcription factor 20 protein. TCF20 regulates gene transcription by acting as a coactivator for a variety of other transcription factors. TCF20 was first associated with autosomal dominant developmental delay with variable intellectual impairment and behavioral abnormalities in 2014 (Babbs et al., PMID 25228304). More than 50 unrelated cases have been reported. The core phenotype of this disorder includes developmental delay / intellectual disability; autism spectrum disorder or other neurobehavioral concerns (e.g. ADHD); dysmorphic facial features; congenital hypotonia; variable neurological disturbances including ataxia, seizures, and movement and sleep disorders; and variable additional features affecting other organ systems. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Haploinsufficiency has been suggested as the mechanism for disease, but a potential dominant-negative mechanism has not been ruled out. This curation included eight unique variants (five frameshift, two stop-gained, one missense) identified in eight unrelated probands from four publications (Babbs et al., 2014 PMID 25228304; Schäfgen et al., 2016 PMID 27436265; Vetrini et al., 2019 PMID 30819258; Torti et al., 2019 PMID 30739909). In the majority of reported cases, variants occurred de novo, but rare cases of a variant inherited from an affected parent have been reported. Notably, two independent evaluations demonstrated that variant transcripts predicted to undergo nonsense-mediated decay (NMD) escaped from NMD. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by TCF20 expression in the brain, a shared structure and biochemical function with another gene associated with a similar phenotype (RAI1) (Vetrini et al., 2019 PMID 30819258), a role in neurogenesis and neural differentiation, and behavioral abnormalities related to autism observed in a heterozygous knockout mouse model (Feng et al., 2020 PMID 32510763). In summary, TCF20 is definitively associated with autosomal dominant developmental delay with variable intellectual impairment and behavioral abnormalities. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on 7.28.2020 (SOP Version 7).

syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: Orphanet

developmental delay with variable intellectual impairment and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032745

Submitter: Illumina

The TCF20 gene is located on chromosome 22 at 22q13.2 and encodes the transcription factor 20 protein. TCF20 regulates gene transcription by acting as a coactivaor for a variety of other transcription factors. TCF20 was first associated with autosomal dominant neurodevelopmental disorders in 2014 (25228304: Babbs et al.2014 ). Evidence supporting this gene-disease relationship includes case-level data and limited experimental data. This curation included seven unique variants (five frameshift and two stop-gained) identified in seven unrelated probands from three publications (25228304: Babbs et al. 2014; 27436265: Schäfgen et al. 2016; 30819258: Vetrini et al. 2019). In the majority of reported cases, variants occurred de novo, but rare cases of a variant inherited from an affected parent have been reported. Notably, two independent evaluations demonstrated that the truncated transcripts escape from nonsense-mediated decay. More genetic evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Haploinsufficiency has been suggested as the mechanism for disease. This gene-disease relationship is also supported by expression in the brain and a shared biochemical function with another gene associated with a similar phenotype (RAI1) (30819258: Vetrini et al. 2019). In summary, there is strong evidence to support the relationship between TCF20 and autosomal dominant TCF20-associated neurodevelopmental disorders. Additional experimental evidence is needed to reach a definitive classification.

developmental delay with variable intellectual impairment and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032745

Submitter: PanelApp Australia

developmental delay with variable intellectual impairment and behavioral abnormalitiesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0032745

Submitter: G2P

Clinical Genomic Database (CGD)

Developmental delay with variable intellectual impairment and behavioral abnormalitiesAD

Manifestation: Craniofacial; Musculoskeletal; 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: 25228304; 27436265; 28135719; 30739909; 30819258

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TCF20 variants in ClinVar

26 Conditions Cataloged

not providedTotal: 978

Inborn genetic diseasesTotal: 285

Developmental delay with variable intellectual impairment and behavioral abnormalitiesTotal: 176

TCF20-related disorderTotal: 56

not specifiedTotal: 52

Neurodevelopmental abnormalityTotal: 15

See casesTotal: 6

Autism spectrum disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001378418.1. 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			4 clinvar	258 clinvar	27 clinvar	289
missense	1 clinvar	4 clinvar	600 clinvar	188 clinvar	25 clinvar	818
nonsense	36 clinvar	12 clinvar	1 clinvar			49
start loss						0
frameshift	72 clinvar	23 clinvar	2 clinvar			97
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	109	39	609	446	52	1255

Highest pathogenic variant AF is 0.0000065748814

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001378418.1	RefSeq	NP_001365347.1	4	MANE Select
ENST00000677622.1	Ensembl	ENSP00000503828.1	4	MANE Select
NM_005650.4	RefSeq	NP_005641.1	4	Standard
NM_181492.3	RefSeq	NP_852469.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Matrix Metalloproteinases

Biological Process

regulation of transcription, DNA-templated
positive regulation of transcription by RNA polymerase II

Molecular Function

DNA binding
DNA-binding transcription factor activity
transcription coactivator activity
RNA binding
protein binding

Cellular Component

nucleus
nucleoplasm
nuclear body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000359486
Coding exons: 4
Length: 183604
Individuals with no LoFs: 125741
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125745
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0895	1048	1.06e+3	0.992	0.0000594	12835
Missense (PolyPhen)		331	409.88	0.80755		5106
Synonymous	-3.14	490	409	1.20	0.0000235	3975
Loss of Function	7.32	2	66.4	0.0301	0.00000368	795

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	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000026	0.000018	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcriptional activator that binds to the regulatory region of MMP3 and thereby controls stromelysin expression. It stimulates the activity of various transcriptional activators such as JUN, SP1, PAX6 and ETS1, suggesting a function as a coactivator.;

Recessive Scores

pRec: 0.194

Intolerance Scores

LoFtool: 0.0597
RVIS EVS: -2.55
RVIS percentile EVS: 0.85

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.602

Gene Damage Prediction

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