RBBP5

protein-coding

RB binding protein 5, histone lysine methyltransferase complex subunit, the group of WD repeat domain containing|WRAD complex

Gene summary

This gene encodes a ubiquitously expressed nuclear protein which belongs to a highly conserved subfamily of WD-repeat proteins. The encoded protein binds directly to retinoblastoma protein, which regulates cell proliferation. It interacts preferentially with the underphosphorylated retinoblastoma protein via the E1A-binding pocket B. Three alternatively spliced transcript variants that encode different protein isoforms have been described for this gene. [provided by RefSeq, Jul 2010]

MANE transcript

NM_005057.4

Inheritance

ClinVar variants

P:2U:30B:5

Top phenotype

neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr1:205,086,142-205,122,015

External References & Databases

Ensembl (ENSG00000117222)

Transcript & Mutation Effects

hg38 • Region Span ~35.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RBBP5 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 24

not providedTotal: 6

RBBP5-related syndromic neurodevelopmental conditionTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005057.4. 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			1 clinvar	4 clinvar		5
missense	1 clinvar		25 clinvar	1 clinvar		27
nonsense	1 clinvar		2 clinvar			3
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	2	0	30	5	0	37

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005057.4	RefSeq	NP_005048.2	14	MANE Select
ENST00000264515.11	Ensembl	ENSP00000264515.6	14	MANE Select
NM_001193272.2	RefSeq	NP_001180201.1	14	Standard
NM_001193273.2	RefSeq	NP_001180202.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cushing,s syndrome - Homo sapiens (human)
Signaling by WNT
Signal Transduction
Gene expression (Transcription)
Generic Transcription Pathway

Biological Process

cellular response to DNA damage stimulus
response to estrogen
post-translational protein modification
regulation of megakaryocyte differentiation
histone H3-K4 methylation

Molecular Function

protein binding
histone-lysine N-methyltransferase activity
methylated histone binding
histone methyltransferase activity (H3-K4 specific)
transcription regulatory region DNA binding

Cellular Component

nucleus
nucleoplasm
nucleolus
histone methyltransferase complex
MLL3/4 complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264515
Coding exons: 14
Length: 35874
Individuals with no LoFs: 125726
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125728
p: 0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.59	119	292	0.408	0.0000151	3508
Missense (PolyPhen)		21	107.25	0.1958		1352
Synonymous	0.804	100	111	0.903	0.00000630	1029
Loss of Function	5.02	2	33.3	0.0601	0.00000195	374

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	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: In embryonic stem (ES) cells, plays a crucial role in the differentiation potential, particularly along the neural lineage, regulating gene induction and H3 'Lys-4' methylation at key developmental loci, including that mediated by retinoic acid (By similarity). As part of the MLL1/MLL complex, involved in mono-, di- and trimethylation at 'Lys-4' of histone H3. Histone H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. {ECO:0000250, ECO:0000269|PubMed:19556245}.;

Recessive Scores

pRec: 0.106

Intolerance Scores

LoFtool: 0.106
RVIS EVS: -0.47
RVIS percentile EVS: 23.04

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.986

Gene Damage Prediction

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