ROBO4

roundabout guidance receptor 4, the group of Fibronectin type III domain containing|I-set domain containing

Basic information

Region (hg38): 11:124883690-124898500

Links

ENSG00000154133 ∙ NCBI:54538 ∙ OMIM:607528 ∙ HGNC:17985 ∙ Uniprot:Q8WZ75 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• aortic valve disease 3 (Strong), mode of inheritance: AD
• aortic valve disease 3 (Strong), mode of inheritance: AD
• aortic valve disease 3 (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Aortic valve disease 3	AD	Cardiovascular	Individuals may have aortic valve and related anomalies (some of which may require surgery), and awareness may allow early diagnosis and management	Cardiovascular	30455415

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ROBO4 gene.

• Inborn genetic diseases (56 variants)
• Familial thoracic aortic aneurysm and aortic dissection (34 variants)
• not provided (24 variants)
• Bicuspid aortic valve;Ascending tubular aorta aneurysm (12 variants)
• Aortic valve disease 3 (11 variants)
• not specified (3 variants)
• ROBO4-related condition (3 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ROBO4 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				5	12	17
missense		7	66	9	11	93
nonsense		1	1			2
start loss						0
frameshift		2	1			3
inframe indel						0
splice donor/acceptor (+/-2bp)		2				2
splice region					1	1
non coding						0
Total	0	12	68	14	23

Highest pathogenic variant AF is 0.0000789

Variants in ROBO4

This is a list of pathogenic ClinVar variants found in the ROBO4 region.

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

Position	Type	Phenotype	Significance	ClinVar
11-124884901-T-C		not specified	Uncertain significance (Dec 27, 2023)
11-124885038-C-T		Familial thoracic aortic aneurysm and aortic dissection • ROBO4-related disorder	Benign (Apr 01, 2024)
11-124885047-C-T		not specified	Uncertain significance (Feb 28, 2023)
11-124885061-C-T		not specified	Uncertain significance (Jan 29, 2024)
11-124885091-T-G		not specified	Uncertain significance (Sep 22, 2023)
11-124885130-C-T		not specified	Uncertain significance (Dec 21, 2023)
11-124885131-G-A		not specified	Uncertain significance (Feb 28, 2023)
11-124885135-G-A		ROBO4-related disorder	Benign (Dec 31, 2019)
11-124885137-T-G		not specified	Uncertain significance (Jul 14, 2023)
11-124885176-A-G		not specified	Uncertain significance (Mar 16, 2022)
11-124885208-A-G		not specified	Uncertain significance (Jul 11, 2023)
11-124885220-T-A		not specified	Uncertain significance (Aug 23, 2021)
11-124885229-G-A		not specified	Uncertain significance (Mar 01, 2024)
11-124886486-C-A		not specified	Uncertain significance (Dec 03, 2021)
11-124886499-C-T		not specified	Uncertain significance (Dec 14, 2023)
11-124886500-C-T		Aortic valve disease 3	Uncertain significance (-)
11-124886501-G-C		not specified	Uncertain significance (May 03, 2023)
11-124886510-G-A		Familial thoracic aortic aneurysm and aortic dissection	Benign (Nov 18, 2022)
11-124886536-G-A		not specified	Uncertain significance (Oct 26, 2022)
11-124886569-C-T		Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Dec 28, 2022)
11-124886622-G-A		not specified	Uncertain significance (Jan 17, 2024)
11-124886697-C-G		not specified	Uncertain significance (Oct 20, 2023)
11-124886697-C-T		not specified	Uncertain significance (Feb 16, 2023)
11-124886787-G-C		not specified	Uncertain significance (May 01, 2022)
11-124887023-C-A		Thoracic aortic aneurysm	Likely pathogenic (-)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ROBO4	protein_coding	protein_coding	ENST00000306534	18	14810

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.94e-15	0.855	125483	0	265	125748	0.00105

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.0903	591	597	0.990	0.0000346	6367
Missense in Polyphen		164	164.59	0.99642		1769
Synonymous	1.14	221	244	0.907	0.0000140	2207
Loss of Function	2.05	30	44.8	0.670	0.00000224	468

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00626	0.00618
Ashkenazi Jewish	0.00	0.00
East Asian	0.000544	0.000544
Finnish	0.0000925	0.0000924
European (Non-Finnish)	0.000793	0.000783
Middle Eastern	0.000544	0.000544
South Asian	0.00119	0.00118
Other	0.000499	0.000489

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Receptor for Slit proteins, at least for SLIT2, and seems to be involved in angiogenesis and vascular patterning. May mediate the inhibition of primary endothelial cell migration by Slit proteins (By similarity). {ECO:0000250}.
• Pathway: Angiogenesis overview;Robo4 and VEGF Signaling Pathways Crosstalk (Consensus)

Recessive Scores

• pRec: 0.129

Intolerance Scores

• loftool: 0.853
• rvis_EVS: 0.66
• rvis_percentile_EVS: 84.2

Haploinsufficiency Scores

• pHI: 0.0905
• hipred: N
• hipred_score: 0.270
• ghis: 0.530

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.743

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Robo4
• Phenotype: 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); 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); muscle phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); cellular phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: robo4
• Affected structure: endocardium
• Phenotype tag: abnormal
• Phenotype quality: malformed

Gene ontology

• Biological process: angiogenesis;homophilic cell adhesion via plasma membrane adhesion molecules;axon guidance;regulation of cell migration;dendrite self-avoidance
• Cellular component: plasma membrane;integral component of membrane;axon;extracellular exosome
• Molecular function: signaling receptor activity;cell-cell adhesion mediator activity