HMGA2
protein-codinghigh mobility group AT-hook 2, the group of Canonical high mobility group
Gene summary
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]
- HMGIC
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~141.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0020795
Submitter: ClinGen
The *HMGA2* (high mobility AT-hook 2) gene located on chromosome 12 at 12q14.3 encodes a encodes a member of the non-histone chromosomal high mobility group (HMG) protein family – architectural factors and essential components of the enhanceosome. Loss of Hmga2 was first reported to be associated with growth restriction in mice (Zhou et al 1995, PMID: 7651535) and microdeletions of 12q had also implicated *HMGA2* as a cause of Silver Russell Syndrome (SRS) (OMIM:618908) (Spengler et al., 2010, PMID: 19762329). SRS diagnosis is based on the Netchine-Harbison clinical scoring system (NH-CSS) from Azzi et al. 2015 (PMID: 25951829) Suggestive findings include intrauterine growth restriction, feeding difficulties in early childhood, and postnatal growth failure. Dysmorphic features include triangular face with frontal bossing or prominent forehead, micrognathia, and relative macrocephaly at birth. Skeletal features include fifth finger clinodactyly and/or small hands. Other findings include high pitched voice, developmental delay, and genitourinary abnormalities (Saal et al., 2025, PMID: 20301499). 9 unique variants from 9 individuals in 5 publications including splice (Gorbenko del Blanco et al., 2011, PMID: 21803798; de Crescenzo et al., 2015, PMID: 25809938), frameshift (Yamoto et a.,l 2024, PMID: 38840187; Maharaj et al., 2024, PMID: 38516887), nonsense and missense variants (PMID: 38516887) have been reported and are included in this curation . Variants in *HMGA2* have been observed to segregate with SRS in families (PMID: 25809938) and also occur de novo (Zhang et al., 2025, PMID: 40393763). More genetic evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence including functional alteration of patient cells (PMID: 21803798) and expression in relevant tissues (Zhou et al., 1995, PMID: 7651535). Several homozygous and heterozygous knockout and knock-in animal models recapitulate growth, cranial, and genitourinary dysmorphology (PMID: 7651535; Lee et al., 2022, PMID: 34878116; PMID: 38516887). In summary, there is definitive evidence supporting the relationship between *HMGA2* and AD SRS. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date June 20th, 2025 (SOP Version 11). The ClinGen preferred term for this condition is *HMGA2*-related Silver-Russell-like syndrome.
Inheritance Pattern: AD
Disease ID:MONDO:0020795
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0020795
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: Unknown
Disease ID:MONDO:0007886
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0020795
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0020795
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Endocrine; Musculoskeletal
Intervention: Endocrine
Rationale: Among other findings, response to growth hormone therapy has been described, and awareness may allow early diagnosis and management of this issue
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HMGA2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003483.6. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 4 | 4 | ||||
| missense | 14 | 1 | 15 | |||
| nonsense | 1 | 1 | 2 | |||
| start loss | 0 | |||||
| frameshift | 3 | 3 | 1 | 7 | ||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 6 | 9 | ||
| Total | 5 | 5 | 22 | 5 | 0 | 37 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003474.1 | 5 | MANE Select | |
| Ensembl | ENSP00000384026.2 | 5 | MANE Select | |
| RefSeq | NP_001287847.1 | 5 | Standard | |
| RefSeq | NP_001287848.1 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- MicroRNAs in cancer - Homo sapiens (human)
- Transcriptional misregulation in cancer - Homo sapiens (human)
- Mesodermal Commitment Pathway
- Formation of Senescence-Associated Heterochromatin Foci (SAHF)
- DNA Damage/Telomere Stress Induced Senescence
Biological Process
- negative regulation of transcription by RNA polymerase II
- epithelial to mesenchymal transition
- chondrocyte differentiation
- mesodermal-endodermal cell signaling
- base-excision repair
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription repressor activity, RNA polymerase II-specific
- DNA-binding transcription activator activity, RNA polymerase II-specific
- DNA binding
Cellular Component
- nuclear chromosome
- nucleus
- nucleoplasm
- protein-DNA complex
- senescence-associated heterochromatin focus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000403681
- Coding exons
- 5
- Length
- 142165
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.34 | 25 | 52.1 | 0.479 | 0.00000259 | 678 |
| Missense (PolyPhen) | 2 | 5.7138 | 0.35003 | 65 | ||
| Synonymous | -2.63 | 33 | 18.6 | 1.78 | 9.82e-7 | 213 |
| Loss of Function | 2.39 | 0 | 6.67 | 0.00 | 2.82e-7 | 91 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Functions as a transcriptional regulator. Functions in cell cycle regulation through CCNA2. Plays an important role in chromosome condensation during the meiotic G2/M transition of spermatocytes. Plays a role in postnatal myogenesis, is involved in satellite cell activation (By similarity). {ECO:0000250|UniProtKB:P52927, ECO:0000269|PubMed:14645522}.;
- Disease
- DISEASE: Note=A chromosomal aberration involving HMGA2 is associated with a subclass of benign mesenchymal tumors known as lipomas. Translocation t(3;12)(q27-q28;q13-q15) with LPP is shown in lipomas. HMGA2 is also fused with a number of other genes in lipomas. {ECO:0000269|PubMed:8824803}.; DISEASE: Note=A chromosomal aberration involving HMGA2 is associated with pulmonary chondroid hamartomas. Translocation t(3;12)(q27-q28;q14-q15) with LPP is detected in pulmonary chondroid hamartomas. {ECO:0000269|PubMed:11066083}.; DISEASE: Note=A chromosomal aberration involving HMGA2 is associated with parosteal lipomas. Translocation t(3;12)(q28;q14) with LPP is also shown in one parosteal lipoma. {ECO:0000269|PubMed:9772904}.; DISEASE: Note=A chromosomal aberration involving HMGA2 is found in uterine leiomyoma. Translocation t(12;14)(q15;q23-24) with RAD51B. Chromosomal rearrangements involving HMGA2 do not seem to be the principle pathobiological mechanism in uterine leiomyoma. {ECO:0000269|PubMed:12649198, ECO:0000269|PubMed:9892177}.;
Recessive Scores
- pRec
- 0.479
Intolerance Scores
- LoFtool
- 0.111
- RVIS EVS
- 0.19
- RVIS percentile EVS
- 66.57
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.199
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |