GTF3C3

Chr 2AR

general transcription factor IIIC subunit 3

Also known as: NEDFBS, TFIIIC102, TFIIICgamma, TFiiiC2-102

NCBI Gene: 9330 ENSG00000119041 UniProt: Q9Y5Q9 OMIM: 604888

The protein is an integral component of the TFIIIC2 complex that directly binds tRNA and viral RNA promoters to recruit RNA polymerase III for transcription of small nuclear and cytoplasmic RNAs. Biallelic mutations cause autosomal recessive neurodevelopmental disorder with dysmorphic facies, brain anomalies, and seizures. The gene is highly constrained against loss-of-function variants (LOEUF 0.588), indicating intolerance to reduced protein function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is part of the TFIIIC2 complex, which binds to the promoters of small nuclear and cytoplasmic RNA genes in order to recruit RNA polymerase III. The TFIIIC2 complex is composed of six subunits. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.591 OMIM phenotype

Clinical Summary— GTF3C3

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

12 unique Pathogenic / Likely Pathogenic· 75 VUS of 124 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.59LOEUF

pLI 0.000

Z-score 3.82

OE 0.40 (0.28–0.59)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.57Z-score

OE missense 0.67 (0.61–0.73)

321 obs / 479.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.40 (0.28–0.59)

0≤0.351.4

Missense OE?0.67 (0.61–0.73)

0≤0.61.4

Synonymous OE?0.81

0≤1.21.6

LoF obs/exp: 19 / 47.4Missense obs/exp: 321 / 479.6Syn Z: 1.89

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateGTF3C3-related neurodevelopmental disorder with hypoplasia of corpus callosum and/or cerebellar atrophyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6745th %ile

GOF

0.6051th %ile

LOF

0.2969th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

124 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic3

VUS75

Likely Benign11

Benign2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	7	1	0	9
Likely Pathogenic	1	1	1	0	3
VUS	1	74	0	0	75
Likely Benign	0	3	3	5	11
Benign	0	1	1	0	2
Total	3	86	6	5	100

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

View in ClinVar →

35 pathogenic / likely-pathogenic (of 40) ClinVar copy-number / structural variants overlap GTF3C3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →