UNG

protein-coding

uracil DNA glycosylase, the group of DNA glycosylases

Gene summary

This gene encodes one of several uracil-DNA glycosylases. One important function of uracil-DNA glycosylases is to prevent mutagenesis by eliminating uracil from DNA molecules by cleaving the N-glycosylic bond and initiating the base-excision repair (BER) pathway. Uracil bases occur from cytosine deamination or misincorporation of dUMP residues. Alternative promoter usage and splicing of this gene leads to two different isoforms: the mitochondrial UNG1 and the nuclear UNG2. The UNG2 term was used as a previous symbol for the CCNO gene (GeneID 10309), which has been confused with this gene, in the literature and some databases. [provided by RefSeq, Nov 2010]

Previous symbols:

MANE transcript

NM_080911.3

Inheritance

AR, AD

ClinVar variants

P:24U:111B:75

Top phenotype

Immunodeficiency with hyper-IgM, type 5

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr12:109,097,597-109,126,725

External References & Databases

Ensembl (ENSG00000076248)

Transcript & Mutation Effects

hg38 • Region Span ~29.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyper-IgM syndrome type 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011971

Submitter: Labcorp Genetics (formerly Invitae)

hyper-IgM syndrome type 5MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011971

Submitter: Ambry Genetics

hyper-IgM syndrome type 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011971

Submitter: PanelApp Australia

hyper-IgM syndrome type 5MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011971

Submitter: ClinGen

UNG was first reported in relation to autosomal hyper-IgM (HIGM) syndrome type 5 in 2003 (Imai K, et al., 2003, PMID: 12958596). Characteristics of HIGM include susceptibility to bacterial infections, lymphoid hyperplasia, increased serum IgM concentrations and profoundly decreased serum IgG and IgA concentrations. Six variants (3 frameshift, 2 missense, and 1 single amino acid deletion) have been reported in five probands in three publications (PMIDs: 12958596, 32135276, 23585684). This gene-disease association is supported by its function as an uracil-DNA glycosylase (PMID: 12214226) with a role in class switch recombination. Additionally, UNG deficiency is linked to a profound inability of human B cells to undergo immunoglobulin class switch recombination in association with qualitative consequences for the pattern of somatic hypermutation (PMID: 12958596) and a mouse model that recapitulates disease (PMID: 12401169). In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.

Clinical Genomic Database (CGD)

Immunodeficiency with hyper-IgM, type 5AD

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Due to low/absent serum IgG, IgA, and IgE, Individuals are susceptible to recurrent/severe bacterial infections, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial

Refs: 12958596; 15358621

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UNG variants in ClinVar

5 Conditions Cataloged

Hyper-IgM syndrome type 5Total: 246

not specifiedTotal: 35

not providedTotal: 23

UNG-related disorderTotal: 5

Hereditary breast ovarian cancer syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_080911.3. 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			3 clinvar	67 clinvar	3 clinvar	73
missense	1 clinvar		103 clinvar	4 clinvar	1 clinvar	109
nonsense	2 clinvar	3 clinvar	2 clinvar			7
start loss						0
frameshift	12 clinvar	2 clinvar	3 clinvar			17
splice donor/acceptor (+/-2bp)		4 clinvar				4
Total	15	9	111	71	4	210

Highest pathogenic variant AF is 0.000035385354

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_080911.3	RefSeq	NP_550433.1	7	MANE Select
ENST00000242576.7	Ensembl	ENSP00000242576.3	7	MANE Select
NM_003362.4	RefSeq	NP_003353.1	6	Standard
ENST00000336865.6	Ensembl	ENSP00000337398.2	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
unga	Danio rerio	Structure: whole organism Quality: deformed abnormal

Gene / Model

Organism

Observed Phenotype

unga

Danio rerio

Structure: whole organism

Quality: deformed

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Primary immunodeficiency - Homo sapiens (human)
Base excision repair - Homo sapiens (human)
DNA Repair
Recognition and association of DNA glycosylase with site containing an affected pyrimidine
Cleavage of the damaged pyrimidine

Biological Process

DNA repair
base-excision repair
viral process
somatic hypermutation of immunoglobulin genes
somatic recombination of immunoglobulin gene segments

Molecular Function

damaged DNA binding
uracil DNA N-glycosylase activity
protein binding
ribosomal small subunit binding

Cellular Component

nucleus
nucleoplasm
mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000242576
Coding exons: 7
Length: 13419
Individuals with no LoFs: 125701
Homozygous LoFs: 0
Heterozygous LoFs: 47
Defined: 125748
p: 0.000187

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0560	173	175	0.988	0.00000871	2031
Missense (PolyPhen)		48	54.873	0.87475		678
Synonymous	-1.69	90	71.8	1.25	0.00000379	609
Loss of Function	2.00	7	15.5	0.452	7.44e-7	178

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0010	0.00092	notable
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00050	0.00050	rare
East Asian	0.00022	0.00022	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00015	0.00013	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Excises uracil residues from the DNA which can arise as a result of misincorporation of dUMP residues by DNA polymerase or due to deamination of cytosine.;
Disease: DISEASE: Immunodeficiency with hyper-IgM 5 (HIGM5) [MIM:608106]: A rare immunodeficiency syndrome characterized by normal or elevated serum IgM levels with absence of IgG, IgA, and IgE. It results in a profound susceptibility to bacterial infections. {ECO:0000269|PubMed:12958596, ECO:0000269|PubMed:15967827}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.456

Intolerance Scores

LoFtool: 0.745
RVIS EVS: -0.47
RVIS percentile EVS: 23.25

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.995

Gene Damage Prediction

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