POU3F3

Chr 2AD

POU class 3 homeobox 3

Also known as: BRN1, OTF8, SNIBFIS, brain-1, oct-8

NCBI Gene: 5455 ENSG00000198914 UniProt: P20264 OMIM: 602480

This transcription factor recognizes octamer DNA sequences and plays a role in neuronal development, acting synergistically with SOX11 and SOX4. Mutations cause Snijders Blok-Fisher syndrome with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 0.88, LOEUF 0.43), reflecting its critical role in nervous system development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a POU-domain containing protein that functions as a transcription factor. The encoded protein recognizes an octamer sequence in the DNA of target genes. This protein may play a role in development of the nervous system. [provided by RefSeq, Apr 2015]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.431 OMIM phenotype

Clinical Summary— POU3F3

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.88) — some intolerance to loss-of-function variants.

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ClinVar Variants

55 unique Pathogenic / Likely Pathogenic· 151 VUS of 246 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?

0.43LOEUF

pLI 0.883

Z-score 2.45

OE 0.00 (0.00–0.43)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.04Z-score

OE missense 0.36 (0.29–0.44)

63 obs / 176.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.43)

0≤0.351.4

Missense OE?0.36 (0.29–0.44)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 0 / 7.0Missense obs/exp: 63 / 176.8Syn Z: -0.60

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePOU3F3-related intellectual disabilityOTHERAD

This gene — mechanism propensity

0.3396th %ile

GOF

0.3193th %ile

LOF

0.90top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 56% of P/LP variants are LoF · LOEUF 0.43

GOF1 literature citation

Literature Evidence

GOFGain-of-function assays showed that the overexpression of lncRNA POU3F3 maintained cell survival with DTIC treatment, while the knockdown of lncRNA POU3F3 restored cell sensitivity to DTIC.1

LOFIn this paper, we discuss the possible role of POU3F3 haploinsufficiency in relation to the boy's phenotype.2

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

References

ClinVar Variant Classifications

246 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16

Likely Pathogenic39

VUS151

Likely Benign36

Benign3

Conflicting1

Pathogenic

Likely Pathogenic

151

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	14	2	0	0	16
Likely Pathogenic	17	22	0	0	39
VUS	3	143	5	0	151
Likely Benign	0	11	3	22	36
Benign	0	1	1	1	3
Conflicting	—				1
Total	34	179	9	23	246

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap POU3F3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →