USF3

Chr 3

upstream transcription factor family member 3

Also known as: KIAA2018

NCBI Gene: 205717 ENSG00000176542 UniProt: Q68DE3 OMIM: 617568

This gene encodes a transcriptional regulator containing a helix-loop-helix domain that negatively regulates epithelial-mesenchymal transition, the process by which epithelial cells lose polarity and become migratory mesenchymal cells. Mutations cause neurodevelopmental disorders with intellectual disability and developmental delay, following an autosomal dominant inheritance pattern. The gene is highly constrained against loss-of-function variants in the population, indicating that such variants are likely to be pathogenic.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a large protein that contains a helix-loop-helix domain and a polyglutamine region. A deletion in the polyglutamine region was associated with risk for thyroid carcinoma. [provided by RefSeq, May 2017]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.19

Clinical Summary— USF3

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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

252 VUS of 296 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.19LOEUF

pLI 1.000

Z-score 6.94

OE 0.10 (0.06–0.19)

Highly constrained

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

Missense Constraint?

0.79Z-score

OE missense 0.93 (0.89–0.98)

1063 obs / 1138.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.10 (0.06–0.19)

0≤0.351.4

Missense OE?0.93 (0.89–0.98)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 7 / 69.3Missense obs/exp: 1063 / 1138.3Syn Z: 0.78

This gene — mechanism propensity

0.2798th %ile

GOF

0.2099th %ile

LOF

0.77top 10%

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

LOFprediction above median · LOEUF 0.19

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

296 submitted variants in ClinVar

ClinVar

Classification Summary

VUS252

Likely Benign20

Benign5

Conflicting4

252

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	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	252	0	0	252
Likely Benign	0	16	0	4	20
Benign	0	4	1	0	5
Conflicting	—				4
Total	0	272	1	4	281

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap USF3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →