DMBX1

Chr 1

diencephalon/mesencephalon homeobox 1

Also known as: Atx, MBX, OTX3, PAXB

NCBI Gene: 127343 ENSG00000197587 UniProt: Q8NFW5 OMIM: 607410

The protein functions as a transcriptional repressor required for brain development, including repression of OTX2-mediated transactivation through heterodimer formation. Mutations cause autosomal recessive developmental and epileptic encephalopathy with microcephaly, affecting brain and sensory organ development. The gene is highly constrained against loss-of-function variants (pLI 0.93, LOEUF 0.37), indicating critical developmental importance.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the bicoid sub-family of homeodomain-containing transcription factors. The encoded protein acts as a transcription factor and may play a role in brain and sensory organ development. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.37

Clinical Summary— DMBX1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.93). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 51 VUS of 62 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.37LOEUF

pLI 0.930

Z-score 3.06

OE 0.08 (0.03–0.37)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.83Z-score

OE missense 0.85 (0.76–0.95)

209 obs / 245.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.08 (0.03–0.37)

0≤0.351.4

Missense OE?0.85 (0.76–0.95)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 1 / 12.9Missense obs/exp: 209 / 245.6Syn Z: 0.18

This gene — mechanism propensity

0.6065th %ile

GOF

0.3292th %ile

LOF

0.72top 10%

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

LOFprediction above median · LOEUF 0.37

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

62 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS51

Likely Benign6

Benign2

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	1	0	1
VUS	51	0	51
Likely Benign	2	4	6
Benign	1	1	2
Total	55	5	60

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap DMBX1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →