PLEKHG5

pleckstrin homology and RhoGEF domain containing G5, the group of Pleckstrin homology domain containing|Dbl family Rho GEFs

Basic information

Region (hg38): 1:6467122-6520074

Links

ENSG00000171680

∙ NCBI:57449 ∙ OMIM:611101 ∙ HGNC:29105 ∙ Uniprot:O94827 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

neuronopathy, distal hereditary motor, autosomal recessive 4 (Limited), mode of inheritance: AR
Charcot-Marie-Tooth disease recessive intermediate C (Moderate), mode of inheritance: AR
neuronopathy, distal hereditary motor, autosomal recessive 4 (Supportive), mode of inheritance: AR
Charcot-Marie-Tooth disease recessive intermediate C (Supportive), mode of inheritance: AR
Charcot-Marie-Tooth disease recessive intermediate C (Strong), mode of inheritance: AR
neuronopathy, distal hereditary motor, autosomal recessive 4 (Strong), mode of inheritance: AR
neuromuscular disease (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Charcot-Marie-Tooth disease, recessive intermediate C; Neuronopathy, distal hereditary motor, autosomal recessive 4	AR	General	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	Musculoskeletal; Neurologic	16728649; 17564964; 23777631; 23844677

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PLEKHG5 gene.

Neuronopathy,_distal_hereditary_motor,_autosomal_recessive_4 (1180 variants)
Charcot-Marie-Tooth_disease_recessive_intermediate_C (1172 variants)
Inborn_genetic_diseases (304 variants)
not_provided (264 variants)
not_specified (101 variants)
PLEKHG5-related_disorder (27 variants)
Distal_spinal_muscular_atrophy (5 variants)
Juvenile_amyotrophic_lateral_sclerosis (2 variants)
Hereditary_motor_neuron_disease (1 variants)
Testicular_atrophy (1 variants)
Hereditary_spastic_paraplegia (1 variants)
Spinal_muscular_atrophy,_facioscapulohumeral_type (1 variants)
Charcot-Marie-Tooth_disease (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PLEKHG5 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000020631.6. Only rare variants are included in the table.

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.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	377 clinvar	2 clinvar	383
missense		4 clinvar	486 clinvar	24 clinvar	5 clinvar	519
nonsense	14 clinvar	9 clinvar	1 clinvar			24
start loss	1		2			3
frameshift	34 clinvar	7 clinvar	1 clinvar	1 clinvar	2 clinvar	45
splice donor/acceptor (+/-2bp)	1 clinvar	15 clinvar				16
Total	50	35	494	402	9

Highest pathogenic variant AF is 0.00046983626

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PLEKHG5	protein_coding	protein_coding	ENST00000537245	22	53970

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000336	1.00	124246	49	1452	125747	0.00599

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.49	552	660	0.837	0.0000450	6913
Missense in Polyphen		226	292.23	0.77337		3105
Synonymous	-0.181	288	284	1.01	0.0000195	2197
Loss of Function	3.94	18	47.2	0.381	0.00000249	546

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0953	0.0856
Ashkenazi Jewish	0.00	0.00
East Asian	0.000165	0.000163
Finnish	0.0000466	0.0000462
European (Non-Finnish)	0.000703	0.000686
Middle Eastern	0.000165	0.000163
South Asian	0.000366	0.000359
Other	0.00264	0.00228

dbNSFP

Source: dbNSFP

Function: FUNCTION: Guanine nucleotide exchange factor that activates RHOA and maybe the NF-kappa-B signaling pathway. Involved in the control of neuronal cell differentiation. Plays a role in angiogenesis through regulation of endothelial cells chemotaxis. {ECO:0000269|PubMed:11704860, ECO:0000269|PubMed:12761501}.;
Disease: DISEASE: Charcot-Marie-Tooth disease, recessive, intermediate type, C (CMTRIC) [MIM:615376]: A form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Recessive intermediate forms of Charcot-Marie-Tooth disease are characterized by clinical and pathologic features intermediate between demyelinating and axonal peripheral neuropathies, and motor median nerve conduction velocities ranging from 25 to 45 m/sec. {ECO:0000269|PubMed:23777631, ECO:0000269|PubMed:23844677}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway: Pathways in cancer - Homo sapiens (human);Signaling by GPCR;Signal Transduction;Rho GTPase cycle;Signaling by Rho GTPases;NRAGE signals death through JNK;Death Receptor Signalling;p75 NTR receptor-mediated signalling;G alpha (12/13) signalling events;GPCR downstream signalling;Cell death signalling via NRAGE, NRIF and NADE (Consensus)

Recessive Scores

pRec: 0.506

Intolerance Scores

loftool: 0.803
rvis_EVS: 1.15
rvis_percentile_EVS: 92.39

Haploinsufficiency Scores

pHI: 0.113
hipred: Y
hipred_score: 0.617
ghis: 0.556

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: N
gene_indispensability_score: 0.375

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Plekhg5
Phenotype: muscle phenotype; homeostasis/metabolism 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); renal/urinary system 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);

Zebrafish Information Network

Gene name: plekhg5b
Affected structure: dorsal longitudinal anastomotic vessel
Phenotype tag: abnormal
Phenotype quality: aplastic

Gene ontology

Biological process: G protein-coupled receptor signaling pathway;regulation of Rho protein signal transduction;endothelial cell chemotaxis;positive regulation of apoptotic process;positive regulation of I-kappaB kinase/NF-kappaB signaling;regulation of small GTPase mediated signal transduction;regulation of protein catabolic process at presynapse, modulating synaptic transmission
Cellular component: cytoplasm;cytosol;plasma membrane;cell-cell junction;lamellipodium;endocytic vesicle;perinuclear region of cytoplasm;presynapse
Molecular function: guanyl-nucleotide exchange factor activity;Rho guanyl-nucleotide exchange factor activity