MBD5

protein-coding

methyl-CpG binding domain protein 5, the group of Methyl-CpG binding domain containing|PWWP domain containing

Gene summary

This gene encodes a member of the methyl-CpG-binding domain (MBD) family. The MBD consists of about 70 residues and is the minimal region required for a methyl-CpG-binding protein binding specifically to methylated DNA. In addition to the MBD domain, this protein contains a PWWP domain (Pro-Trp-Trp-Pro motif), which consists of 100-150 amino acids and is found in numerous proteins that are involved in cell division, growth and differentiation. Mutations in this gene cause an autosomal dominant type of cognitive disability. The encoded protein interacts with the polycomb repressive complex PR-DUB which catalyzes the deubiquitination of a lysine residue of histone 2A. Haploinsufficiency of this gene is associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures. Alternatively spliced transcript variants have been found, but their full-length nature is not determined. [provided by RefSeq, Jul 2017]

MANE transcript

NM_001378120.1

Inheritance

ClinVar variants

P:136U:929B:656

Top phenotype

Intellectual developmental disorder, autosomal dominant 1

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr2:148,021,011-148,516,971

External References & Databases

Ensembl (ENSG00000204406)

Transcript & Mutation Effects

hg38 • Region Span ~496.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*MBD5* haploinsufficiency due to an intragenic deletion was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2007 (PMID: 17847001). This curation includes heterozygous deletions encompassing all or part of *MBD5* and *MBD5* truncating variants (PMID: 27786435). Duplications encompassing the entire *MBD5* have also been reported in individuals with neurodevelopmental disorders; as these typically also involve other genes and are likely acting via a different molecular mechanism, they are not included in this curation. Individuals with *MBD5* pathogenic variants present with developmental delay, intellectual disability, epilepsy, autism spectrum disorder, severe speech impairment, and behavioral problems (PMIDs: 23422940, 27786435, 33912662). Over 100 individuals with neurodevelopmental disorders and *MBD5* LoF variants have been reported in the literature (PMIDs: 17847001, 22495309, 22726846, 23422940, 23708187, 25356899, 27848944, 28807762, 29778030, 30763456, 32193494, 32238909, 33912662), but only 11 probands are included in this curation because the maximum score for genetic evidence has been reached. Most variants are *de novo*, although inheritance from parents with low level mosaicism has been reported in multiple affected individuals with *MBD5* LoF variants (PMIDs: 32238909, 33912662, 36396431). There have also been reports of probands with intragenic *MBD5* duplications (PMIDs: 23422940, 33912662), and expression analysis in one patient showed that the encoded aberrant transcripts resulted in premature termination (PMID: 23422940). The mechanism for disease is predicted to be haploinsufficiency (PMID: 23422940). The gene-disease relationship is also supported by experimental evidence, including a mouse model and a cell culture model (PMID: 25001218). In summary, there is definitive evidence to support the relationship between *MBD5* and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 15, 2023 (SOP Version 9). This gene-disease pair was originally evaluated on November 21, 2018 and classified as moderate. Curation of additional genetic evidence resulted in the classification being updated

autosomal dominant non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015802

Submitter: Orphanet

complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: PanelApp Australia

intellectual disability, autosomal dominant 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007974

Submitter: G2P

intellectual disability, autosomal dominant 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007974

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 1AD

Manifestation: Craniofacial; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 17847001; 21981781

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MBD5 variants in ClinVar

21 Conditions Cataloged

Intellectual disability, autosomal dominant 1Total: 1428

not providedTotal: 556

Inborn genetic diseasesTotal: 254

not specifiedTotal: 192

MBD5-related disorderTotal: 67

Intellectual disabilityTotal: 12

See casesTotal: 6

MBD5 associated neurodevelopmental disorderTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001378120.1. 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			10 clinvar	381 clinvar	3 clinvar	394
missense	1 clinvar	6 clinvar	907 clinvar	261 clinvar	11 clinvar	1186
nonsense	27 clinvar	14 clinvar	3 clinvar			44
start loss		1 clinvar				1
frameshift	53 clinvar	25 clinvar	4 clinvar			82
splice donor/acceptor (+/-2bp)	4 clinvar	5 clinvar	5 clinvar			14
Total	85	51	929	642	14	1721

Highest pathogenic variant AF is 0.000010261266

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001378120.1	RefSeq	NP_001365049.1	10	MANE Select
ENST00000642680.2	Ensembl	ENSP00000493871.2	10	MANE Select
NM_001438854.1	RefSeq	NP_001425783.1	10	Standard
NM_001438855.1	RefSeq	NP_001425784.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein modification
Metabolism of proteins
UCH proteinases
Deubiquitination

Biological Process

nervous system development
protein deubiquitination
regulation of multicellular organism growth
glucose homeostasis
regulation of behavior

Molecular Function

DNA binding
chromatin binding

Cellular Component

nucleus
nucleoplasm
chromocenter
midbody
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000407073
Coding exons: 10
Length: 497226
Individuals with no LoFs: 125742
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125746
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.856	710	777	0.914	0.0000403	9822
Missense (PolyPhen)		35	42.073	0.83188		419
Synonymous	-0.611	301	288	1.05	0.0000161	3033
Loss of Function	6.04	2	46.4	0.0431	0.00000244	595

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binds to heterochromatin. Does not interact with either methylated or unmethylated DNA (in vitro).;
Disease: DISEASE: Mental retardation, autosomal dominant 1 (MRD1) [MIM:156200]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:17847001, ECO:0000269|PubMed:22726846}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0958

Intolerance Scores

LoFtool: 0.0116
RVIS EVS: -2.12
RVIS percentile EVS: 1.52

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.936

Gene Damage Prediction

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