BRAP

protein-coding

BRCA1 associated protein, the group of Ring finger proteins

Gene summary

The protein encoded by this gene was identified by its ability to bind to the nuclear localization signal of BRCA1 and other proteins. It is a cytoplasmic protein which may regulate nuclear targeting by retaining proteins with a nuclear localization signal in the cytoplasm. [provided by RefSeq, Jul 2008]

MANE transcript

NM_006768.5

Inheritance

AR, AD

ClinVar variants

U:69B:7

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr12:111,642,146-111,685,956

External References & Databases

Ensembl (ENSG00000089234)

Transcript & Mutation Effects

hg38 • Region Span ~43.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cardiomyopathyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0004994

Submitter: LiferaOmics

Genetic evidence: Published case (PMID: 31130284): homozygous nonsense NM_006768.4:c.199C>T; p.(Arg67Ter) with non-immune hydrops fetalis only = 0.5 points (phenotype lacks documented cardiac involvement; scored conservatively for a cardiac-primary disease entity). Our case: homozygous frameshift NM_006768.5:c.113dup; p.(Thr39AspfsTer37) in a consanguineous family = 1.0 point (AR predicted/proven null = 1.5, −0.5 downgrade for homozygosity/consanguinity). Segregation = 0 (no genotyped affected relatives provided); case-control = 0 Experimental evidence = 3.0 points, supported by cardiac-relevant animal model and functional data, including global and cardiomyocyte-specific Brap knockout causing embryonic lethality and lethal cardiac failure/dilated cardiomyopathy phenotypes (PMID: 31286143), demonstrating requirement of BRAP for cardiomyocyte proliferation and survival. Protein Interaction = 0.5 (PMID: 23673330). Overall score = 5 points

pulmonary arterial hypertensionLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BRAP variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 63

not providedTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006768.5. 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		6 clinvar	7
missense			65 clinvar	1 clinvar		66
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	69	1	6	76

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_006768.5	RefSeq	NP_006759.3	12	MANE Select
ENST00000419234.9	Ensembl	ENSP00000403524.3	12	MANE Select
ENST00000327551.6	Ensembl	ENSP00000330813.5	11	Standard
ENST00000327551.7	Ensembl	ENSP00000330813.5	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ras signaling pathway - Homo sapiens (human)
Ras Signaling
RAF activation
Disease
Signal Transduction

Biological Process

MAPK cascade
Ras protein signal transduction
negative regulation of signal transduction
protein ubiquitination

Molecular Function

nucleic acid binding
ubiquitin-protein transferase activity
protein binding
nuclear localization sequence binding
zinc ion binding

Cellular Component

ubiquitin ligase complex
cytoplasm
cytosol
nuclear membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000419234
Coding exons: 12
Length: 43841
Individuals with no LoFs: 125719
Homozygous LoFs: 0
Heterozygous LoFs: 29
Defined: 125748
p: 0.000115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.89	246	344	0.714	0.0000196	3916
Missense (PolyPhen)		65	125.42	0.51826		1390
Synonymous	0.134	126	128	0.985	0.00000772	1076
Loss of Function	3.05	15	34.3	0.437	0.00000199	384

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00012	0.00011	rare
South Asian	0.00013	0.00013	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Negatively regulates MAP kinase activation by limiting the formation of Raf/MEK complexes probably by inactivation of the KSR1 scaffold protein. Also acts as a Ras responsive E3 ubiquitin ligase that, on activation of Ras, is modified by auto- polyubiquitination resulting in the release of inhibition of Raf/MEK complex formation. May also act as a cytoplasmic retention protein with a role in regulating nuclear transport. {ECO:0000269|PubMed:14724641, ECO:0000303|PubMed:10777491}.;

Recessive Scores

pRec: 0.339

Intolerance Scores

LoFtool: 0.745
RVIS EVS: -0.51
RVIS percentile EVS: 21.56

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.921

Gene Damage Prediction

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