MBD4

methyl-CpG binding domain 4, DNA glycosylase, the group of DNA glycosylases|Methyl-CpG binding domain containing

Basic information

Region (hg38): 3:129430947-129440179

Links

ENSG00000129071 ∙ NCBI:8930 ∙ OMIM:603574 ∙ HGNC:6919 ∙ Uniprot:O95243 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• tumor predisposition syndrome 2 (Moderate), mode of inheritance: AR
• tumor predisposition syndrome 2 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Uveal melanoma, susceptibility to, 1; Tumor predisposition syndrome 2	AD/AR	Oncologic	Uveal melanoma, susceptibility to involves increased risk of uveal melanoma, and awareness may enable early identification and management (positive response to pembrolizumab has been described); Tumor predisposition syndrome 2 can involve increased risk of a number of different types of cancer, including hematologic malignancy as well as solid tumors, and awareness may enable early identification and management of cancer-related manifestations	Oncologic	29760383; 30049810; 30714079; 31322271; 32239153; 35460607
Heterozygous variants can also be involved in predisposition to uveal melanoma

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MBD4 gene.

• not provided (26 variants)
• Tumor predisposition syndrome 2 (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MBD4 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			2	63	2	67
missense			191	2	4	197
nonsense	6		4			10
start loss						0
frameshift	20					20
inframe indel			7			7
splice donor/acceptor (+/-2bp)		4	1			5
splice region			6	4	1	11
non coding			5	32	10	47
Total	26	4	210	97	16

Highest pathogenic variant AF is 0.000197

Variants in MBD4

This is a list of pathogenic ClinVar variants found in the MBD4 region.

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

Position	Type	Phenotype	Significance	ClinVar
3-129431510-A-C			Uncertain significance (Dec 17, 2023)
3-129431522-A-G			Likely benign (Dec 05, 2023)
3-129431523-T-C			Uncertain significance (Nov 03, 2023)
3-129431538-C-T		Melanoma, uveal, susceptibility to, 1	Uncertain significance (Oct 29, 2023)
3-129431540-G-A			Likely benign (Jan 24, 2024)
3-129431542-C-G		not specified	Conflicting classifications of pathogenicity (Aug 01, 2024)
3-129431544-T-C			Uncertain significance (Mar 19, 2023)
3-129431545-G-A			Uncertain significance (Jan 20, 2023)
3-129431547-T-C			Uncertain significance (Jan 28, 2024)
3-129431549-T-C			Likely benign (Dec 27, 2023)
3-129431556-A-T		Melanoma, uveal, susceptibility to, 1 • Tumor predisposition syndrome 2	Conflicting classifications of pathogenicity (Jan 29, 2024)
3-129431559-T-C			Uncertain significance (Dec 27, 2023)
3-129431588-A-G			Uncertain significance (Dec 12, 2023)
3-129431590-A-G			Uncertain significance (Jan 24, 2024)
3-129431595-A-C			Uncertain significance (Jan 17, 2024)
3-129431596-T-C			Likely benign (Dec 10, 2023)
3-129431598-C-G			Likely benign (Dec 18, 2023)
3-129431751-A-C			Benign (May 13, 2021)
3-129432443-G-A		MBD4-related disorder	Likely benign (Dec 30, 2022)
3-129432483-T-C			Likely benign (Jan 04, 2024)
3-129432487-T-C			Likely benign (Jun 09, 2022)
3-129432490-G-C			Likely benign (Jan 18, 2024)
3-129432492-G-A			Likely benign (Nov 25, 2023)
3-129432500-C-T			Uncertain significance (Jan 02, 2024)
3-129432513-T-A			Uncertain significance (Dec 06, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MBD4	protein_coding	protein_coding	ENST00000249910	8	9092

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.97e-14	0.0573	125670	0	78	125748	0.000310

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.460	270	292	0.924	0.0000150	3817
Missense in Polyphen		70	87.459	0.80037		1197
Synonymous	-1.17	118	103	1.15	0.00000534	1064
Loss of Function	0.585	23	26.2	0.877	0.00000151	342

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000535	0.000535
Ashkenazi Jewish	0.000198	0.000198
East Asian	0.000761	0.000761
Finnish	0.000185	0.000185
European (Non-Finnish)	0.000360	0.000360
Middle Eastern	0.000761	0.000761
South Asian	0.0000980	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Mismatch-specific DNA N-glycosylase involved in DNA repair. Has thymine glycosylase activity and is specific for G:T mismatches within methylated and unmethylated CpG sites. Can also remove uracil or 5-fluorouracil in G:U mismatches. Has no lyase activity. Was first identified as methyl-CpG-binding protein. {ECO:0000269|PubMed:10097147, ECO:0000269|PubMed:10930409}.
• 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: 0.177

Intolerance Scores

• loftool: 0.304
• rvis_EVS: 0.62
• rvis_percentile_EVS: 83.42

Haploinsufficiency Scores

• pHI: 0.425
• hipred: N
• hipred_score: 0.341
• ghis: 0.499

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.986

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mbd4
• Phenotype: embryo phenotype; neoplasm; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); vision/eye 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); limbs/digits/tail phenotype; digestive/alimentary phenotype; cellular phenotype; homeostasis/metabolism phenotype; growth/size/body region phenotype; craniofacial phenotype

Gene ontology

• Biological process: DNA repair;response to radiation;response to estradiol;depyrimidination
• Cellular component: chromatin;nucleus;nucleoplasm;nuclear speck
• Molecular function: DNA binding;satellite DNA binding;endodeoxyribonuclease activity;protein binding;pyrimidine-specific mismatch base pair DNA N-glycosylase activity;DNA N-glycosylase activity