TNRC6B

protein-coding

trinucleotide repeat containing adaptor 6B, the group of Armadillo like helical domain containing|TNRC6 adaptor family

Gene summary

Enables RNA binding activity. Involved in positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay; positive regulation of nuclear-transcribed mRNA poly(A) tail shortening; and regulatory ncRNA-mediated gene silencing. Acts upstream of with a positive effect on miRNA-mediated gene silencing by inhibition of translation. Predicted to be located in cytosol. Predicted to be active in P-body and nucleoplasm. Implicated in subserous uterine fibroid and uterine fibroid. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_001162501.2

Inheritance

ClinVar variants

P:73U:414B:112

Top phenotype

Global developmental delay with speech and behavioral abnormalities

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr22:40,044,817-40,335,808

External References & Databases

Ensembl (ENSG00000100354)

Transcript & Mutation Effects

hg38 • Region Span ~291.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: Orphanet

global developmental delay with speech and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030995

Submitter: PanelApp Australia

global developmental delay with speech and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030995

Submitter: Labcorp Genetics (formerly Invitae)

global developmental delay with speech and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030995

Submitter: G2P

global developmental delay with speech and behavioral abnormalitiesMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0030995

Submitter: Ambry Genetics

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

De novo truncating variants in TNRC6B were first reported in humans with autosomal dominant complex neurodevelopmental disorder in 2014 (Iossifov et al., PMID: 25363768). Individuals with pathogenic variants in this gene have presented with neurodevelopmental phenotypes including intellectual disability, autism spectrum disorder, motor and speech delay, and attention deficit-hyperactivity disorder. Evidence supporting this gene-disease relationship was derived from case-level data. Protein truncating variants in this gene have been reported in over 25 individuals with neurodevelopmental disorders;10 probands from 3 publications (PMIDs: 25363768, 29463886, 32152250) are included in this curation, though additional genetic evidence is available in the literature (PMIDs: 27479843, 30564305, 33057194, 28191889). At least six de novo TNRC6B missense variants have been reported in individuals with neurodevelopmental disorders (PMIDs: 28135719, 31981491) but were not scored because their functional significance is unknown. The mechanism for disease is predicted to be haploinsufficiency based on the predominance of protein truncating variants among individuals with neurodevelopmental disorders. To date, there is no experimental evidence to directly support the role of this gene in neurodevelopmental disorders. In summary, there is sufficient genetic evidence to support a definitive gene-disease relationship between TNRC6B and complex neurodevelopmental disorder. The classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 1/6/21 (SOP Version 8).

Clinical Genomic Database (CGD)

Global developmental delay with speech 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: 29463886; 32152250

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TNRC6B variants in ClinVar

17 Conditions Cataloged

not providedTotal: 249

Inborn genetic diseasesTotal: 221

Global developmental delay with speech and behavioral abnormalitiesTotal: 104

TNRC6B-related disorderTotal: 58

not specifiedTotal: 20

Global developmental delayTotal: 3

Neurodevelopmental disorderTotal: 2

Autism spectrum disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001162501.2. 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			12 clinvar	46 clinvar	2 clinvar	60
missense	1 clinvar	1 clinvar	385 clinvar	60 clinvar	4 clinvar	451
nonsense	19 clinvar	13 clinvar	8 clinvar			40
start loss			1 clinvar			1
frameshift	17 clinvar	16 clinvar	3 clinvar			36
splice donor/acceptor (+/-2bp)	3 clinvar	3 clinvar	5 clinvar			11
Total	40	33	414	106	6	599

Highest pathogenic variant AF is 0.0000020526406

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001162501.2	RefSeq	NP_001155973.1	23	MANE Select
ENST00000454349.7	Ensembl	ENSP00000401946.2	23	MANE Select
NM_001024843.2	RefSeq	NP_001020014.1	22	Standard
NM_015088.3	RefSeq	NP_055903.2	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Competing endogenous RNAs (ceRNAs) regulate PTEN translation
Signal Transduction
Gene expression (Transcription)
Generic Transcription Pathway
Oncogene Induced Senescence

Biological Process

Wnt signaling pathway, calcium modulating pathway
positive regulation of gene expression
negative regulation of gene expression
gene silencing by RNA
posttranscriptional gene silencing by RNA

Molecular Function

RNA binding
protein binding

Cellular Component

P-body
nucleoplasm
cytosol
micro-ribonucleoprotein complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000454349
Coding exons: 23
Length: 290992
Individuals with no LoFs: 124654
Homozygous LoFs: 0
Heterozygous LoFs: 23
Defined: 124677
p: 0.0000922

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.87	733	987	0.743	0.0000522	11944
Missense (PolyPhen)		238	383.7	0.62028		4603
Synonymous	-0.216	390	385	1.01	0.0000228	3617
Loss of Function	7.95	9	90.7	0.0992	0.00000485	928

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0012	0.00058	notable
Latino/Admixed American	0.00029	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000056	0.000055	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000047	0.000035	rare
South Asian	0	0.0	absent
Other	0.00017	0.00017	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in RNA-mediated gene silencing by both micro-RNAs (miRNAs) and short interfering RNAs (siRNAs). Required for miRNA-dependent translational repression and siRNA-dependent endonucleolytic cleavage of complementary mRNAs by argonaute family proteins. As scaffoldng protein associates with argonaute proteins bound to partially complementary mRNAs and simultaneously can recruit CCR4-NOT and PAN deadenylase complexes. {ECO:0000269|PubMed:16289642, ECO:0000269|PubMed:19167051, ECO:0000269|PubMed:19304925, ECO:0000269|PubMed:21981923}.;

Recessive Scores

pRec: 0.119

Intolerance Scores

LoFtool: 0.377
RVIS EVS: -1.81
RVIS percentile EVS: 2.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.867

Gene Damage Prediction

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