PLEKHG5

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

Basic information

Region (hg38): 1:6467121-6520074

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;Charcot-Marie-Tooth disease recessive intermediate C (572 variants)
• not provided (271 variants)
• Inborn genetic diseases (222 variants)
• Charcot-Marie-Tooth disease recessive intermediate C;Neuronopathy, distal hereditary motor, autosomal recessive 4 (187 variants)
• Neuronopathy, distal hereditary motor, autosomal recessive 4 (107 variants)
• not specified (92 variants)
• Charcot-Marie-Tooth disease recessive intermediate C (18 variants)
• Distal spinal muscular atrophy (6 variants)
• Juvenile amyotrophic lateral sclerosis (2 variants)
• PLEKHG5-related condition (2 variants)
• Testicular atrophy (1 variants)
• Peripheral neuropathy (1 variants)
• Spinal muscular atrophy, facioscapulohumeral type (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.

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			6	158	5	169
missense		1	424	9	9	443
nonsense	7	4	2			13
start loss			2			2
frameshift	16	3	1	1	1	22
inframe indel			20	4	2	26
splice donor/acceptor (+/-2bp)		5				5
splice region			22	23	4	49
non coding			18	113	52	183
Total	23	13	473	285	69

Highest pathogenic variant AF is 0.0000460

Variants in PLEKHG5

This is a list of pathogenic ClinVar variants found in the PLEKHG5 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-6467200-G-C		Neuronopathy, distal hereditary motor, autosomal recessive 4	Uncertain significance (Jan 13, 2018)
1-6467259-G-A		Neuronopathy, distal hereditary motor, autosomal recessive 4	Uncertain significance (Jan 12, 2018)
1-6467273-A-G		Neuronopathy, distal hereditary motor, autosomal recessive 4	Benign (Jun 14, 2018)
1-6467278-G-A		Neuronopathy, distal hereditary motor, autosomal recessive 4	Uncertain significance (Jan 12, 2018)
1-6467327-C-T		Neuronopathy, distal hereditary motor, autosomal recessive 4	Uncertain significance (Jan 13, 2018)
1-6467371-C-T		Neuronopathy, distal hereditary motor, autosomal recessive 4	Uncertain significance (Jan 12, 2018)
1-6467404-C-T		Neuronopathy, distal hereditary motor, autosomal recessive 4	Uncertain significance (Jan 12, 2018)
1-6467455-C-T		Neuronopathy, distal hereditary motor, autosomal recessive 4	Benign/Likely benign (Jun 28, 2018)
1-6467495-G-A		Neuronopathy, distal hereditary motor, autosomal recessive 4	Uncertain significance (Jan 13, 2018)
1-6467500-G-A		Neuronopathy, distal hereditary motor, autosomal recessive 4	Benign (Jan 13, 2018)
1-6467536-A-G		Neuronopathy, distal hereditary motor, autosomal recessive 4	Benign (Jan 13, 2018)
1-6467551-G-A			Likely benign (Jul 31, 2017)
1-6467569-C-T		Neuronopathy, distal hereditary motor, autosomal recessive 4;Charcot-Marie-Tooth disease recessive intermediate C	Uncertain significance (Jul 11, 2022)
1-6467575-A-G		Inborn genetic diseases	Uncertain significance (Mar 17, 2021)
1-6467577-AGGGTGGGGAGGG-A		Neuronopathy, distal hereditary motor, autosomal recessive 4;Charcot-Marie-Tooth disease recessive intermediate C	Uncertain significance (Aug 31, 2021)
1-6467579-G-A		Neuronopathy, distal hereditary motor, autosomal recessive 4;Charcot-Marie-Tooth disease recessive intermediate C	Likely benign (Mar 10, 2023)
1-6467582-G-A		Neuronopathy, distal hereditary motor, autosomal recessive 4;Charcot-Marie-Tooth disease recessive intermediate C	Likely benign (May 27, 2023)
1-6467583-G-C		Charcot-Marie-Tooth disease recessive intermediate C;Neuronopathy, distal hereditary motor, autosomal recessive 4	Likely benign (Dec 01, 2023)
1-6467584-G-A		Neuronopathy, distal hereditary motor, autosomal recessive 4;Charcot-Marie-Tooth disease recessive intermediate C	Likely benign (Nov 11, 2023)
1-6467587-G-C		Neuronopathy, distal hereditary motor, autosomal recessive 4;Charcot-Marie-Tooth disease recessive intermediate C	Likely benign (Jan 27, 2024)
1-6467589-G-A		Neuronopathy, distal hereditary motor, autosomal recessive 4;Charcot-Marie-Tooth disease recessive intermediate C	Likely benign (Jan 13, 2023)
1-6467590-G-A		Neuronopathy, distal hereditary motor, autosomal recessive 4;Charcot-Marie-Tooth disease recessive intermediate C	Likely benign (Aug 29, 2023)
1-6467651-G-A			Likely benign (Jun 19, 2018)
1-6467685-C-T			Benign (Jun 18, 2018)
1-6467765-G-T			Likely benign (Aug 15, 2018)

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