HMGA2

Chr 12AD

high mobility group AT-hook 2

Also known as: BABL, HMGI-C, HMGIC, LIPO, SRS5, STQTL9

NCBI Gene: 8091 ENSG00000149948 UniProt: P52926 OMIM: 600698

HMGA2 encodes a transcriptional regulator that controls cell cycle progression and positively regulates IGF2 expression. Mutations cause Silver-Russell syndrome 5, a growth disorder characterized by prenatal and postnatal growth restriction, with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants, indicating intolerance to complete protein loss.

OMIM ResearchSummary from OMIM, UniProt

This gene encodes a protein that belongs to the non-histone chromosomal high mobility group (HMG) protein family. HMG proteins function as architectural factors and are essential components of the enhancesome. This protein contains structural DNA-binding domains and may act as a transcriptional regulating factor. Identification of the deletion, amplification, and rearrangement of this gene that are associated with myxoid liposarcoma suggests a role in adipogenesis and mesenchymal differentiation. A gene knock out study of the mouse counterpart demonstrated that this gene is involved in diet-induced obesity. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.451 OMIM phenotype

Clinical Summary— HMGA2

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Gene-Disease Validity (ClinGen)

Silver-Russell syndrome 5 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.87) — some intolerance to loss-of-function variants.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.45LOEUF

pLI 0.870

Z-score 2.39

OE 0.00 (0.00–0.45)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.34Z-score

OE missense 0.48 (0.35–0.67)

25 obs / 52.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.45)

0≤0.351.4

Missense OE?0.48 (0.35–0.67)

0≤0.61.4

Synonymous OE?1.78

0≤1.21.6

LoF obs/exp: 0 / 6.7Missense obs/exp: 25 / 52.1Syn Z: -2.63

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongHMGA2-related Silver-Russell-like syndromeLOFAD

This gene — mechanism propensity

0.2897th %ile

GOF

0.10100th %ile

LOF

0.77top 5%

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

LOFprediction above median · 1 literature citation · LOEUF 0.45

Literature Evidence

LOFWe suggest that HMGA2 mutations leading to haploinsufficiency should be investigated in the SRS patients negative for the typical 11p15 (epi)mutations and matUPD7.1

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

References