NTHL1

nth like DNA glycosylase 1, the group of DNA glycosylases

Basic information

Region (hg38): 16:2039814-2047866

Links

ENSG00000065057 ∙ NCBI:4913 ∙ OMIM:602656 ∙ HGNC:8028 ∙ Uniprot:P78549 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• familial adenomatous polyposis 3 (Strong), mode of inheritance: AR
• familial adenomatous polyposis 3 (Strong), mode of inheritance: AR
• familial adenomatous polyposis 3 (Supportive), mode of inheritance: AR
• familial adenomatous polyposis 3 (Definitive), mode of inheritance: AR
• NTHL1-deficiency tumor predisposition syndrome (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Familial adenomatous polyposis 3	AR	Oncologic	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	Oncologic	25938944; 26559593

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NTHL1 gene.

• not provided (1135 variants)
• Hereditary cancer-predisposing syndrome (778 variants)
• Familial adenomatous polyposis 3 (187 variants)
• not specified (68 variants)
• NTHL1-related condition (11 variants)
• NTHL1-related conditions (1 variants)
• Lymphangiomyomatosis;Tuberous sclerosis 2;Isolated focal cortical dysplasia type II (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NTHL1 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	276		281
missense			677	3		680
nonsense	22	13	2			37
start loss			9			9
frameshift	44	25	5			74
inframe indel			15			15
splice donor/acceptor (+/-2bp)		15	2			17
splice region			36	31	2	69
non coding			11	121	4	136
Total	66	53	726	400	4

Highest pathogenic variant AF is 0.0000263

Variants in NTHL1

This is a list of pathogenic ClinVar variants found in the NTHL1 region.

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

Position	Type	Phenotype	Significance	ClinVar
16-2039893-C-T		not specified	Likely benign (Aug 15, 2023)
16-2039894-A-G		not specified	Likely benign (Aug 15, 2023)
16-2039918-C-A			Likely benign (Apr 30, 2019)
16-2039924-T-C		Hereditary cancer-predisposing syndrome	Uncertain significance (Mar 10, 2021)
16-2039925-C-T		Hereditary cancer-predisposing syndrome	Likely benign (Mar 18, 2021)
16-2039925-CAG-C		Hereditary cancer-predisposing syndrome	Uncertain significance (Jun 27, 2023)
16-2039926-A-G			Uncertain significance (Jul 14, 2023)
16-2039925-C-CAG		Hereditary cancer-predisposing syndrome	Uncertain significance (Mar 13, 2022)
16-2039928-A-T		Hereditary cancer-predisposing syndrome	Uncertain significance (Aug 27, 2023)
16-2039929-G-T			Uncertain significance (Jan 22, 2022)
16-2039930-A-G		Hereditary cancer-predisposing syndrome	Likely benign (Sep 27, 2023)
16-2039930-AC-TT			Uncertain significance (Feb 25, 2020)
16-2039931-C-A			Uncertain significance (Apr 08, 2022)
16-2039931-C-G			Uncertain significance (Jan 21, 2020)
16-2039931-C-T			Uncertain significance (Apr 24, 2023)
16-2039932-C-G		Hereditary cancer-predisposing syndrome	Conflicting classifications of pathogenicity (Feb 22, 2024)
16-2039932-C-T		Hereditary cancer-predisposing syndrome	Uncertain significance (Feb 12, 2022)
16-2039933-C-G			Uncertain significance (Jul 06, 2022)
16-2039933-C-T		Hereditary cancer-predisposing syndrome	Likely benign (Aug 04, 2022)
16-2039934-T-A			Uncertain significance (Mar 07, 2021)
16-2039934-TGGGCGGCC-T			Uncertain significance (Dec 29, 2021)
16-2039935-G-A		Familial adenomatous polyposis 3	Uncertain significance (Nov 15, 2023)
16-2039935-G-C			Uncertain significance (Jun 02, 2022)
16-2039936-G-C			Likely benign (Sep 01, 2022)
16-2039937-G-A		Hereditary cancer-predisposing syndrome	Uncertain significance (Apr 23, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NTHL1	protein_coding	protein_coding	ENST00000219066	6	8052

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
5.66e-10	0.0662	125322	0	409	125731	0.00163

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.797	233	201	1.16	0.0000125	1995
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00147	0.00146
Ashkenazi Jewish	0.000696	0.000695
East Asian	0.000109	0.000109
Finnish	0.00386	0.00384
European (Non-Finnish)	0.00222	0.00221
Middle Eastern	0.000109	0.000109
South Asian	0.000327	0.000327
Other	0.00180	0.00179

dbNSFP

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.
• Pathway: 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;Base-Excision Repair, AP Site Formation;Resolution of Abasic Sites (AP sites);Base Excision Repair;Displacement of DNA glycosylase by APEX1 (Consensus)

Recessive Scores

• pRec: 0.216

Intolerance Scores

• loftool: 0.373
• rvis_EVS: -0.58
• rvis_percentile_EVS: 18.59

Haploinsufficiency Scores

• pHI: 0.754
• hipred: N
• hipred_score: 0.239
• ghis: 0.544

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.997

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nthl1
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: base-excision repair, AP site formation;nucleotide-excision repair, DNA incision, 5'-to lesion;depyrimidination
• Cellular component: nucleus;nucleoplasm;mitochondrion
• 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;oxidized purine nucleobase lesion DNA N-glycosylase activity;DNA N-glycosylase activity;metal ion binding;4 iron, 4 sulfur cluster binding;class I DNA-(apurinic or apyrimidinic site) endonuclease activity