TNRC6A

Chr 16AD

trinucleotide repeat containing adaptor 6A

Also known as: CAGH26, FAME6, GW1, GW182, TNRC6

NCBI Gene: 27327 ENSG00000090905 UniProt: Q8NDV7 OMIM: 610739

The protein functions as a scaffolding component in RNA-mediated gene silencing, recruiting deadenylase complexes and associating with argonaute proteins to enable microRNA and siRNA-mediated translational repression and mRNA cleavage. Mutations cause autosomal dominant neurodevelopmental disorder with seizures, developmental delay, and intellectual disability. This gene is highly intolerant to loss-of-function mutations, indicating that proper dosage is critical for normal development.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the trinucleotide repeat containing 6 protein family. The protein functions in post-transcriptional gene silencing through the RNA interference (RNAi) and microRNA pathways. The protein associates with messenger RNAs and Argonaute proteins in cytoplasmic bodies known as GW-bodies or P-bodies. Inhibiting expression of this gene delocalizes other GW-body proteins and impairs RNAi and microRNA-induced gene silencing. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.161 OMIM phenotype

Clinical Summary— TNRC6A

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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

1 unique Pathogenic / Likely Pathogenic· 271 VUS of 336 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.16LOEUF

pLI 1.000

Z-score 8.38

OE 0.09 (0.05–0.16)

Highly constrained

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

Missense Constraint?

1.13Z-score

OE missense 0.90 (0.85–0.95)

951 obs / 1054.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.09 (0.05–0.16)

0≤0.351.4

Missense OE?0.90 (0.85–0.95)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 9 / 98.9Missense obs/exp: 951 / 1054.4Syn Z: -0.71

This gene — mechanism propensity

0.2199th %ile

GOF

0.3193th %ile

LOF

0.87top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.16

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

ClinVar Variant Classifications

336 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS271

Likely Benign12

Benign12

Conflicting3

Pathogenic

271

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	1	0	1
Likely Pathogenic	0	0	0	0	0
VUS	1	267	1	2	271
Likely Benign	0	8	1	3	12
Benign	0	6	2	4	12
Conflicting	—				3
Total	1	281	5	9	299

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap TNRC6A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →