NTHL1

protein-coding

nth like DNA glycosylase 1, the group of DNA glycosylases

Gene summary

The protein encoded by this gene is a DNA N-glycosylase of the endonuclease III family. Like a similar protein in E. coli, the encoded protein has DNA glycosylase activity on DNA substrates containing oxidized pyrimidine residues and has apurinic/apyrimidinic lyase activity. [provided by RefSeq, Oct 2008]

MANE transcript

NM_002528.7

Inheritance

ClinVar variants

P:168U:917B:406

Top phenotype

Familial adenomatous polyposis 3

gnomAD constraint

pLI —, LoF o/e 1.03

Max pathogenic AF

—

Genomic locus

chr16:2,039,815-2,047,866

External References & Databases

Ensembl (ENSG00000065057)

Transcript & Mutation Effects

hg38 • Region Span ~8.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial adenomatous polyposis 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014630

Submitter: Ambry Genetics

familial adenomatous polyposis 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014630

Submitter: Labcorp Genetics (formerly Invitae)

familial adenomatous polyposis 3SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014630

Submitter: Orphanet

NTHL1-deficiency tumor predisposition syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100502

Submitter: ClinGen

*NTHL*1 plays a role in base-excision repair pathway and was first reported in relation to autosomal recessive NTHL1-deficiency tumor predisposition syndrome in 2015 (Weren et al., PMID: 25938944). The condition is primarily characterized by adenomatous polyposis of colon (~10-50), colorectal cancer, and breast cancer. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found NTHL1-deficiency tumor predisposition syndrome (MONDO:0100502) is the only one disease entity associated with this gene. About 30 individuals carrying biallelic loss-of-function variants, most commonly NM_002528.7(NTHL1):c.244C>T (p.Gln82Ter) (formerly referred to as p.Gln90Ter) in line with its relatively high minor allele frequency (~0.1%) in the population databases, have been reported to date and 5 of them along with their affected siblings are included in this curation (PMIDs: 25938944, 30753826, 27720914, 26559593). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity has been demonstrated to be loss-of-function resulting in deficient NTHL1 activity (PMID: 25938944). A specific mutational signature due to a high percentage of somatic C>T transitions (COSMIS Signature 30) in cancer driver genes such as *KRAS, APC, TP53, PIK3CA* has been identified on tested tumor samples, and the preliminary data also suggest other primary tumors, i.e. urothelial carcinoma of the bladder, might also be linked to *NTHL1* deficiency per mutational profiling of such tumors (PMID: 30753826). This gene-disease relationship is also supported by experimental evidence (3.85 points from human cell models, in vitro functional assays, animal models, etc.) (PMIDs: 8990169, 19346169, 30552997, 28912133). Particularly, human colonic stem cells-derived organoids devoid of NTHL1 activity phenocopied the somatic mutational signature detected in tumoral samples of individuals carrying biallelic loss-of-function *NTHL1* variants. In summary, *NTHL1* is definitively associated with autosomal recessive NTHL1-deficiency tumor predisposition syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

breast cancerLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0007254

Submitter: Ambry Genetics

meningiomaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0016642

Submitter: Ambry Genetics

familial adenomatous polyposis 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014630

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Familial adenomatous polyposis 3AR

Manifestation: Oncologic

Intervention: Oncologic

Rationale: Individuals have been described as affected by multiple types of cancer, including colorectal cancer, endometrial cancer, and other neoplasms, and awareness may allow surveillance and early management

Refs: 25938944; 26559593

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NTHL1 variants in ClinVar

13 Conditions Cataloged

not providedTotal: 1383

Hereditary cancer-predisposing syndromeTotal: 1196

Familial adenomatous polyposis 3Total: 287

not specifiedTotal: 106

NTHL1-related disorderTotal: 82

NTHL1-deficiency tumor predisposition syndromeTotal: 8

Inherited polyposis and early onset colorectal cancer - germline testingTotal: 6

Hereditary cancerTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002528.7. 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			9 clinvar	353 clinvar		362
missense		1 clinvar	888 clinvar	53 clinvar		942
nonsense	24 clinvar	20 clinvar	3 clinvar			47
start loss			8 clinvar			8
frameshift	74 clinvar	26 clinvar	7 clinvar			107
splice donor/acceptor (+/-2bp)		23 clinvar	2 clinvar			25
Total	98	70	917	406	0	1491

Highest pathogenic variant AF is 0.0015918671

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 44 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002528.7	RefSeq	NP_002519.2	6	MANE Select
ENST00000651570.2	Ensembl	ENSP00000498421.1	6	MANE Select
NM_001318193.2	RefSeq	NP_001305122.2	5	Standard
NM_001318194.2	RefSeq	NP_001305123.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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
Depyrimidination

Biological Process

base-excision repair, AP site formation
nucleotide-excision repair, DNA incision, 5'-to lesion
depyrimidination

Molecular Function

oxidized pyrimidine nucleobase lesion DNA N-glycosylase activity
double-stranded DNA binding
DNA-(apurinic or apyrimidinic site) endonuclease activity
endonuclease activity
protein binding

Cellular Component

nucleus
nucleoplasm
mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000219066
Coding exons: 6
Length: 8052
Individuals with no LoFs: 125322
Homozygous LoFs: 0
Heterozygous LoFs: 409
Defined: 125731
p: 0.00163

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.797	233	201	1.16	0.0000125	1995
Missense (PolyPhen)		51	52.414	0.97302		546
Synonymous	0.409	84	88.9	0.945	0.00000615	645
Loss of Function	-0.0975	14	13.6	1.03	6.68e-7	146

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.0012	0.0012	notable
Ashkenazi Jewish	0.00070	0.00069	rare
East Asian	0.00011	0.00011	rare
Finnish	0.0039	0.0038	notable
European (Non-Finnish)	0.0022	0.0022	notable
South Asian	0.00033	0.00033	rare
Other	0.0018	0.0018	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Bifunctional DNA N-glycosylase with associated apurinic/apyrimidinic (AP) lyase function that catalyzes the first step in base excision repair (BER), the primary repair pathway for the repair of oxidative DNA damage. The DNA N-glycosylase activity releases the damaged DNA base from DNA by cleaving the N- glycosidic bond, leaving an AP site. The AP-lyase activity cleaves the phosphodiester bond 3' to the AP site by a beta-elimination. Primarily recognizes and repairs oxidative base damage of pyrimidines. Has also 8-oxo-7,8-dihydroguanine (8-oxoG) DNA glycosylase activity. Acts preferentially on DNA damage opposite guanine residues in DNA. Is able to process lesions in nucleosomes without requiring or inducing nucleosome disruption. {ECO:0000255|HAMAP-Rule:MF_03183, ECO:0000269|PubMed:10882850, ECO:0000269|PubMed:11328882, ECO:0000269|PubMed:11380260, ECO:0000269|PubMed:11695910, ECO:0000269|PubMed:12140329, ECO:0000269|PubMed:12144783, ECO:0000269|PubMed:12519758, ECO:0000269|PubMed:14734554, ECO:0000269|PubMed:15533839, ECO:0000269|PubMed:17923696, ECO:0000269|PubMed:20005182, ECO:0000269|PubMed:20110254, ECO:0000269|PubMed:21930793, ECO:0000269|PubMed:8990169, ECO:0000269|PubMed:9045706, ECO:0000269|PubMed:9705289, ECO:0000269|PubMed:9890904}.;
Disease: DISEASE: Familial adenomatous polyposis 3 (FAP3) [MIM:616415]: A form of familial adenomatous polyposis, a condition characterized by the development of multiple colorectal adenomatous polyps, benign neoplasms derived from glandular epithelium. Some affected individuals may develop colorectal carcinoma. {ECO:0000269|PubMed:25938944}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.216

Intolerance Scores

LoFtool: 0.373
RVIS EVS: -0.58
RVIS percentile EVS: 18.59

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.997

Gene Damage Prediction

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