MBD4

Chr 3ADAR

methyl-CpG binding domain 4, DNA glycosylase

Also known as: MED1, TPDS2, UVM1

NCBI Gene: 8930 ENSG00000129071 UniProt: O95243 OMIM: 603574

The protein encoded by this gene is a member of a family of nuclear proteins related by the presence of a methyl-CpG binding domain (MBD). These proteins are capable of binding specifically to methylated DNA, and some members can also repress transcription from methylated gene promoters. This protein contains an MBD domain at the N-terminus that functions both in binding to methylated DNA and in protein interactions and a C-terminal mismatch-specific glycosylase domain that is involved in DNA repair. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2013]

GeneReviews OMIM Research

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

{Uveal melanoma, susceptibility to, 1}MIM #606660

Tumor predisposition syndrome 2MIM #619975

UniProtMelanoma, uveal, 1

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.24

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — MBD4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.24LOEUF

pLI 0.000

Z-score 0.58

OE 0.88 (0.63–1.24)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.46Z-score

OE missense 0.92 (0.84–1.02)

270 obs / 292.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.88 (0.63–1.24)

0≤0.351.4

Missense OE?0.92 (0.84–1.02)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 23 / 26.2Missense obs/exp: 270 / 292.1Syn Z: -1.17

Background carrier burden — how many people carry a rare variant somewhere in MBD4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

682 rare PASS variants

Rare truncating (LoF)

1 in 270

157 rare PASS variants

Rare synonymous (reference)

1 in 220

259 rare PASS variants

Rare missense and truncating variants are carried at similar rates in MBD4; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 180	1 in 290
South Asian	~43k	1 in 92	1 in 440
Remaining (unassigned)	~30k	1 in 110	1 in 310
European (Finnish)	~27k	1 in 230	1 in 950
Admixed American	~22k	1 in 100	1 in 280
African / African American	~21k	1 in 84	1 in 210
East Asian	~20k	1 in 73	1 in 350
Ashkenazi Jewish	~13k	1 in 130	1 in 1,000
Middle Eastern	~2,884	1 in 83	1 in 220

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 8 coding exons well covered in gnomAD exomes and genomes.? see exons ↓