HMGA2

high mobility group AT-hook 2, the group of Canonical high mobility group

Basic information

Region (hg38): 12:65824460-65966291

Previous symbols: [ "HMGIC" ]

Links

ENSG00000149948 ∙ NCBI:8091 ∙ OMIM:600698 ∙ HGNC:5009 ∙ Uniprot:P52926 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• uterine corpus leiomyoma (No Known Disease Relationship), mode of inheritance: Unknown
• Silver-Russell syndrome 5 (Limited), mode of inheritance: AD
• Silver-Russell syndrome 5 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Silver-Russell syndrome 5	AD	Endocrine	Among other findings, response to growth hormone therapy has been described, and awareness may allow early diagnosis and management of this issue	Craniofacial; Endocrine; Musculoskeletal	28567303; 28796236; 29501611; 29655892

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HMGA2 gene.

• Silver-Russell syndrome 5 (3 variants)
• not provided (1 variants)
• Silver-Russell syndrome 1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HMGA2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				5		5
missense			6	1	1	8
nonsense	2			1		3
start loss						0
frameshift	1	1	1			3
inframe indel						0
splice donor/acceptor (+/-2bp)			1			1
splice region			2	1		3
non coding				2	2	4
Total	3	1	8	9	3

Variants in HMGA2

This is a list of pathogenic ClinVar variants found in the HMGA2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-65825285-T-G		HMGA2-related disorder	Likely benign (Jun 10, 2019)
12-65825310-TCAGCC-T		Silver-Russell syndrome 5	Likely pathogenic (Sep 01, 2022)
12-65825316-C-CA		Silver-Russell syndrome 5	Pathogenic (Aug 01, 2021)
12-65825387-T-A		Silver-Russell syndrome 5	Uncertain significance (Feb 23, 2023)
12-65828027-GAGA-CT		Silver-Russell syndrome 5	Pathogenic (May 01, 2024)
12-65828043-C-A		not specified	Uncertain significance (Dec 18, 2023)
12-65828043-C-T			Uncertain significance (Apr 29, 2022)
12-65828068-C-T			Uncertain significance (Dec 05, 2023)
12-65828077-CA-C		Silver-Russell syndrome 1 • Silver-Russell syndrome 5	Pathogenic (Feb 13, 2024)
12-65828082-C-T		Silver-Russell syndrome 1 • Silver-Russell syndrome 5	Pathogenic (Oct 24, 2022)
12-65828088-G-A		Silver-Russell syndrome 5	Uncertain significance (Apr 10, 2024)
12-65838511-A-G		HMGA2-related disorder • Silver-Russell syndrome 5	Benign/Likely benign (May 17, 2022)
12-65838532-C-T		not specified	Uncertain significance (Jul 28, 2021)
12-65838543-C-T			Uncertain significance (Jun 13, 2022)
12-65838551-A-G			Likely benign (Aug 07, 2017)
12-65838569-GGTGA-G		Silver-Russell syndrome 5	Uncertain significance (Jan 21, 2022)
12-65914894-C-T			Likely benign (Feb 01, 2023)
12-65915081-G-A			Uncertain significance (Mar 29, 2023)
12-65915116-A-G		HMGA2-related disorder	Benign (May 23, 2019)
12-65915135-T-C		HMGA2-related disorder	Benign (Jun 17, 2019)
12-65951407-C-G		HMGA2-related disorder	Likely benign (Dec 31, 2019)
12-65951424-T-C			Likely benign (Jun 21, 2018)
12-65952348-T-C			Likely benign (Jul 01, 2024)
12-65952427-T-C		HMGA2-related disorder	Benign (May 23, 2019)
12-65963237-TGTTCCAG-T		Silver-Russell syndrome 5	Pathogenic (Jun 12, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HMGA2	protein_coding	protein_coding	ENST00000403681	5	142165

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.870	0.128	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.34	25	52.1	0.479	0.00000259	678
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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}.
• Pathway: 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;Cellular Senescence;Cellular responses to stress;Cellular responses to external stimuli (Consensus)

Recessive Scores

• pRec: 0.479

Intolerance Scores

• loftool: 0.111
• rvis_EVS: 0.19
• rvis_percentile_EVS: 66.57

Haploinsufficiency Scores

• pHI: 0.557
• hipred: Y
• hipred_score: 0.599
• ghis: 0.477

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.199

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Hmga2
• Phenotype: homeostasis/metabolism phenotype; craniofacial phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); hearing/vestibular/ear phenotype; limbs/digits/tail phenotype; reproductive system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;epithelial to mesenchymal transition;chondrocyte differentiation;mesodermal-endodermal cell signaling;base-excision repair;chromatin organization;regulation of transcription, DNA-templated;mitotic G2 DNA damage checkpoint;multicellular organism development;response to virus;regulation of cell cycle process;positive regulation of gene expression;chromosome condensation;chromosome breakage;heterochromatin assembly;histone H2A-S139 phosphorylation;senescence-associated heterochromatin focus assembly;endodermal cell differentiation;chondrocyte proliferation;regulation of growth;DNA damage response, detection of DNA damage;positive regulation of apoptotic process;negative regulation of apoptotic process;negative regulation of DNA binding;negative regulation by host of viral transcription;fat cell differentiation;positive regulation of angiogenesis;negative regulation of single stranded viral RNA replication via double stranded DNA intermediate;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;mesodermal cell differentiation;mesenchymal cell differentiation;stem cell differentiation;cell division;positive regulation of cell cycle arrest;positive regulation of cell proliferation in bone marrow;positive regulation of protein serine/threonine kinase activity;oncogene-induced cell senescence;regulation of stem cell population maintenance;positive regulation of stem cell proliferation;positive regulation of transcription regulatory region DNA binding;positive regulation of cellular response to X-ray;negative regulation of cellular senescence;positive regulation of cellular senescence;positive regulation of response to DNA damage stimulus;negative regulation of double-strand break repair via nonhomologous end joining;regulation of cellular response to drug
• Cellular component: nuclear chromosome;nucleus;nucleoplasm;protein-DNA complex;senescence-associated heterochromatin focus;SMAD protein complex
• 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;AT DNA binding;transcription coregulator activity;DNA-(apurinic or apyrimidinic site) endonuclease activity;protein binding;transcription factor binding;DNA binding, bending;nucleosomal DNA binding;cAMP response element binding;MH2 domain binding;MH1 domain binding;transcription regulatory region DNA binding;SMAD binding;5'-deoxyribose-5-phosphate lyase activity;C2H2 zinc finger domain binding