PLEKHM1

pleckstrin homology and RUN domain containing M1, the group of Pleckstrin homology domain containing

Basic information

Region (hg38): 17:45435900-45490758

Links

ENSG00000225190

∙ NCBI:9842 ∙ OMIM:611466 ∙ HGNC:29017 ∙ Uniprot:Q9Y4G2 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

osteopetrosis, autosomal dominant 3 (Limited), mode of inheritance: AD
autosomal recessive osteopetrosis 6 (Limited), mode of inheritance: AR
autosomal recessive osteopetrosis 6 (Supportive), mode of inheritance: AR
osteopetrosis, autosomal dominant 3 (Limited), mode of inheritance: Unknown
osteopetrosis, autosomal dominant 3 (Limited), mode of inheritance: AD
autosomal recessive osteopetrosis 6 (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Osteopetrosis, autosomal dominant 3; Osteopetrosis, autosomal recessive 6	AD/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	17404618; 17997709; 27291868

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PLEKHM1 gene.

not_specified (142 variants)
not_provided (8 variants)
Osteopetrosis,_autosomal_dominant_3 (6 variants)
Autosomal_recessive_osteopetrosis_6 (3 variants)
Autosomal_recessive_osteopetrosis_1 (1 variants)
Increased_bone_mineral_density (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PLEKHM1 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000014798.3. 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			1 clinvar	2 clinvar	1 clinvar	4
missense	1 clinvar		135 clinvar	10 clinvar		146
nonsense		1 clinvar				1
start loss						0
frameshift	1 clinvar		1 clinvar			2
splice donor/acceptor (+/-2bp)	1 clinvar					1
Total	3	1	137	12	1

Highest pathogenic variant AF is 0.00000185892

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PLEKHM1	protein_coding	protein_coding	ENST00000430334	11	54850

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00814	0.992	125721	0	27	125748	0.000107

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.18	531	613	0.866	0.0000408	6850
Missense in Polyphen		160	220.9	0.72431		2500
Synonymous	0.781	259	275	0.940	0.0000188	2194
Loss of Function	4.25	12	41.6	0.288	0.00000200	475

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000946	0.0000904
Ashkenazi Jewish	0.000198	0.000198
East Asian	0.0000544	0.0000544
Finnish	0.000139	0.000139
European (Non-Finnish)	0.000145	0.000141
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000980	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

Function: FUNCTION: Proposed to act as a multivalent adapter protein that regulates Rab7-dependent and HOPS complex-dependent fusion events in the endolysosomal system and couples autophagic and the endocytic trafficking pathways. Required for late stages of endolysosomal maturation, facilitating both endocytosis-mediated degradation of growth factor receptors and autophagosome clearance. Seems to be involved in the terminal maturation of autophagosomes and to mediate autophagosome-lysosome fusion (PubMed:25498145). Positively regulates lysosome peripheral distribution and ruffled border formation in osteoclasts (By similarity). May be involved in negative regulation of endocytic transport from early endosome to late endosome/lysosome implicating its association with Rab7 (PubMed:20943950). May have a role in sialyl-lex-mediated transduction of apoptotic signals (PubMed:12820725). Involved in bone resorption (By similarity). In case of infection contributes to Salmonella typhimurium pathogenesis by supporting the integrity of the Salmonella- containing vacuole (SCV) probably in concert with the HOPS complex and Rab7 (PubMed:25500191). {ECO:0000250|UniProtKB:Q5PQS0, ECO:0000250|UniProtKB:Q7TSI1, ECO:0000269|PubMed:12820725, ECO:0000269|PubMed:20943950, ECO:0000269|PubMed:25498145, ECO:0000269|PubMed:25500191, ECO:0000305}.;
Disease: DISEASE: Osteopetrosis, autosomal recessive 6 (OPTB6) [MIM:611497]: A rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. Osteopetrosis occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Recessive osteopetrosis commonly manifests in early infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, bone marrow failure, severe anemia, and hepatosplenomegaly. Deafness and blindness are generally thought to represent effects of pressure on nerves. {ECO:0000269|PubMed:17404618}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

loftool: 0.503
rvis_EVS: -1.53
rvis_percentile_EVS: 3.41

Haploinsufficiency Scores

pHI: 0.113
hipred: Y
hipred_score: 0.685
ghis: 0.490

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: S
essential_gene_gene_trap: N
gene_indispensability_pred: E
gene_indispensability_score: 0.745

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Plekhm1
Phenotype: hematopoietic system phenotype; normal phenotype; renal/urinary system phenotype; skeleton phenotype; immune system phenotype; limbs/digits/tail phenotype; 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); adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); cellular phenotype;

Gene ontology

Biological process: autophagy;protein transport;lysosome localization;intracellular signal transduction;positive regulation of bone resorption;positive regulation of ruffle assembly
Cellular component: nucleolus;lysosomal membrane;endosome membrane;intracellular membrane-bounded organelle
Molecular function: metal ion binding