IRX3

Chr 16

iroquois homeobox 3

Also known as: IRX-1, IRXB1

NCBI Gene: 79191 ENSG00000177508 UniProt: P78415

IRX3 is a member of the Iroquois homeobox gene family (see IRX1; MIM 606197) and plays a role in an early step of neural development (Bellefroid et al., 1998 [PubMed 9427753]). Members of this family appear to play multiple roles during pattern formation of vertebrate embryos (Lewis et al., 1999 [PubMed 10370142]).[supplied by OMIM, Aug 2009]

Active trials

Pathogenic / LP

ClinVar variants

Pubs (1 yr)

0.6

Missense Z

0.41

LOEUF

Clinical Summary— IRX3

⚡

Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.89) — some intolerance to loss-of-function variants.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.41LOEUF

pLI 0.892

Z-score 2.88

OE 0.09 (0.03–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

0.58Z-score

OE missense 0.89 (0.79–1.00)

191 obs / 215.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.09 (0.03–0.41)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.89 (0.79–1.00)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.13

0≤1.21.6

LoF obs/exp: 1 / 11.6Missense obs/exp: 191 / 215.0Syn Z: -1.06

0.4190th %ile

GOF

0.2895th %ile

LOF

0.79top 5%

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

LOFprediction above median · LOEUF 0.41

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