GeneBe

ARHGAP35

protein-coding

Rho GTPase activating protein 35, the group of Rho GTPase activating proteins

Gene summary

The human glucocorticoid receptor DNA binding factor, which associates with the promoter region of the glucocorticoid receptor gene (hGR gene), is a repressor of glucocorticoid receptor transcription. The amino acid sequence deduced from the cDNA sequences show the presence of three sequence motifs characteristic of a zinc finger and one motif suggestive of a leucine zipper in which 1 cysteine is found instead of all leucines. The GRLF1 enhances the homologous down-regulation of wild-type hGR gene expression. Biochemical analysis suggests that GRLF1 interaction is sequence specific and that transcriptional efficacy of GRLF1 is regulated through its interaction with specific sequence motif. The level of expression is regulated by glucocorticoids. [provided by RefSeq, Jul 2008]

Previous symbols:
  • GRLF1

MANE transcript

NM_004491.5

Inheritance

AD

ClinVar variants

P:23U:148B:25

Top phenotype

neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr19:46,860,997-47,005,077

External References & Databases

Ensembl (ENSG00000160007)NCBI Gene (2909)OMIM (605277)HGNC:4591GenCCUniProt (Q9NRY4)AlphaFoldClinVar (ARHGAP35)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~144.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

multiple congenital anomalies/dysmorphic syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019042

Submitter: Ambry Genetics

neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: Ambry Genetics

developmental defect of the eyeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020145

Submitter: PanelApp Australia

neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

congenital hypogonadotropic hypogonadismSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015770

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ARHGAP35 variants in ClinVar

13 Conditions Cataloged
not specifiedTotal: 148
not providedTotal: 17
Martsolf syndrome 1Total: 17
ARHGAP35-related conditionTotal: 5
Neurodevelopmental disorderTotal: 2
Bilateral microphthalmosTotal: 1
ARHGAP35-related disorderTotal: 1
Irido-corneo-trabecular dysgenesisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004491.5. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
16
clinvar
3
clinvar
 20
missense
2
clinvar
137
clinvar
6
clinvar
 145
nonsense
4
clinvar
6
clinvar
2
clinvar
 12
start loss
0
frameshift
7
clinvar
4
clinvar
5
clinvar
 16
splice donor/acceptor (+/-2bp)
3
clinvar
 3
Total1112148223196

Highest pathogenic variant AF is 0.000006572634

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_004491.5RefSeqNP_004482.46MANE Select
ENST00000672722.1EnsemblENSP00000500409.16MANE Select
ENST00000862299.1EnsemblENSP00000532358.16Standard
ENST00000862299.2EnsemblENSP00000532358.16Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Platelet activation - Homo sapiens (human)
  • Focal adhesion - Homo sapiens (human)
  • Regulation of actin cytoskeleton - Homo sapiens (human)
  • Leukocyte transendothelial migration - Homo sapiens (human)
  • Focal Adhesion

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • neural tube closure
  • transcription, DNA-templated
  • signal transduction
  • axon guidance

Molecular Function

  • RNA polymerase II regulatory region sequence-specific DNA binding
  • DNA-binding transcription repressor activity, RNA polymerase II-specific
  • DNA binding
  • transcription corepressor activity
  • GTPase activity

Cellular Component

  • nucleus
  • cytosol
  • plasma membrane
  • actin cytoskeleton
  • ciliary basal body

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000404338
Coding exons
6
Length
86402
Individuals with no LoFs
124634
Homozygous LoFs
0
Heterozygous LoFs
4
Defined
124638
p
0.0000160
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense4.165108520.5990.00004979949
Missense (PolyPhen)136356.040.381974119
Synonymous0.1533343380.9890.00002062906
Loss of Function6.68052.00.000.00000310609

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000270.000027rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Rho GTPase-activating protein (GAP) (PubMed:19673492, PubMed:28894085). Binds several acidic phospholipids which inhibits the Rho GAP activity to promote the Rac GAP activity (PubMed:19673492). This binding is inhibited by phosphorylation by PRKCA (PubMed:19673492). Involved in cell differentiation as well as cell adhesion and migration, plays an important role in retinal tissue morphogenesis, neural tube fusion, midline fusion of the cerebral hemispheres and mammary gland branching morphogenesis (By similarity). Transduces signals from p21-ras to the nucleus, acting via the ras GTPase-activating protein (GAP) (By similarity). Transduces SRC-dependent signals from cell-surface adhesion molecules, such as laminin, to promote neurite outgrowth. Regulates axon outgrowth, guidance and fasciculation (By similarity). Modulates Rho GTPase-dependent F-actin polymerization, organization and assembly, is involved in polarized cell migration and in the positive regulation of ciliogenesis and cilia elongation (By similarity). During mammary gland development, is required in both the epithelial and stromal compartments for ductal outgrowth (By similarity). Represses transcription of the glucocorticoid receptor by binding to the cis-acting regulatory sequence 5'-GAGAAAAGAAACTGGAGAAACTC-3'; this function is however unclear and would need additional experimental evidences (PubMed:1894621). {ECO:0000250|UniProtKB:P81128, ECO:0000250|UniProtKB:Q91YM2, ECO:0000269|PubMed:1894621, ECO:0000269|PubMed:19673492, ECO:0000269|PubMed:28894085}.;

Recessive Scores

pRec
0.167

Intolerance Scores

RVIS EVS
-1.81
RVIS percentile EVS
2.17

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.114

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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