HMGB3

protein-coding

high mobility group box 3, the group of Canonical high mobility group

Gene summary

This gene encodes a member of a family of proteins containing one or more high mobility group DNA-binding motifs. The encoded protein plays an important role in maintaining stem cell populations, and may be aberrantly expressed in tumor cells. A mutation in this gene was associated with microphthalmia, syndromic 13. There are numerous pseudogenes of this gene on multiple chromosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

Previous symbols:

HMG4

MANE transcript

NM_005342.4

Inheritance

ClinVar variants

U:36B:4

Top phenotype

Microphthalmia, syndromic 13

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:150,980,509-150,990,771

External References & Databases

Ensembl (ENSG00000029993)

Transcript & Mutation Effects

hg38 • Region Span ~10.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndromeLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0010485

Submitter: G2P

X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndromeLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0010485

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Microphthalmia, syndromic 13XL

Manifestation: Craniofacial; Dental; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 4998085; 24993872

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HMGB3 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 15

not providedTotal: 10

HMGB3-related disorderTotal: 4

X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndromeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005342.4. 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 clinvar	3 clinvar	1 clinvar	8
missense			24 clinvar			24
nonsense						0
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	0	0	36	3	1	40

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 65 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005342.4	RefSeq	NP_005333.2	4	MANE Select
ENST00000325307.12	Ensembl	ENSP00000359393.3	4	MANE Select
NM_001301228.2	RefSeq	NP_001288157.1	4	Standard
NM_001301229.2	RefSeq	NP_001288158.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

DNA recombination
chromatin remodeling
regulation of transcription by RNA polymerase II
multicellular organism development
DNA geometric change

Molecular Function

four-way junction DNA binding
double-stranded DNA binding
RNA binding
protein binding
transcription factor binding

Cellular Component

nuclear chromatin
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000325307
Coding exons: 4
Length: 10267
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	1.78	32	75.4	0.424	0.00000596	1340
Missense (PolyPhen)		0	12.781	0		328
Synonymous	-1.86	39	26.8	1.46	0.00000213	331
Loss of Function	2.13	0	5.29	0.00	3.98e-7	118

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: dbNSFP

Function: FUNCTION: Multifunctional protein with various roles in different cellular compartments. May act in a redox sensitive manner. Associates with chromatin and binds DNA with a preference to non- canonical DNA structures such as single-stranded DNA. Can bent DNA and enhance DNA flexibility by looping thus providing a mechanism to promote activities on various gene promoters (By similarity). Proposed to be involved in the innate immune response to nucleic acids by acting as a cytoplasmic promiscuous immunogenic DNA/RNA sensor (By similarity). Negatively regulates B-cell and myeloid cell differentiation. In hematopoietic stem cells may regulate the balance between self-renewal and differentiation. Involved in negative regulation of canonical Wnt signaling (By similarity). {ECO:0000250|UniProtKB:O54879, ECO:0000250|UniProtKB:P09429, ECO:0000250|UniProtKB:P40618}.;
Disease: DISEASE: Microphthalmia, syndromic, 13 (MCOPS13) [MIM:300915]: A form of microphthalmia, a disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues (anophthalmia). In many cases, microphthalmia/anophthalmia occurs in association with syndromes that include non-ocular abnormalities. MCOPS13 patients exhibit colobomatous microphthalmia with microcephaly, short stature, and psychomotor retardation. {ECO:0000269|PubMed:24993872}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.142

Intolerance Scores

LoFtool: 0.172
RVIS EVS: -0.03
RVIS percentile EVS: 51.04

Essentials

Essential (CRISPR): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.307

Gene Damage Prediction

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