PLEKHM1

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

Basic information

Region (hg38): 17:45435899-45490758

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.

• Inborn genetic diseases (47 variants)
• not provided (25 variants)
• Osteopetrosis, autosomal dominant 3;Autosomal recessive osteopetrosis 6 (1 variants)
• not specified (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.

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	6
missense			45	5		50
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			1			1
non coding					14	14
Total	0	0	45	5	20

Variants in PLEKHM1

This is a list of pathogenic ClinVar variants found in the PLEKHM1 region.

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

Position	Type	Phenotype	Significance	ClinVar
17-45437588-G-A			Benign (Nov 12, 2018)
17-45437861-G-A			Likely benign (-)
17-45437870-G-T		not specified	Uncertain significance (Nov 10, 2022)
17-45437874-T-C		not specified	Uncertain significance (Dec 07, 2021)
17-45437892-C-T		not specified	Uncertain significance (Sep 06, 2022)
17-45439372-A-C			Benign (Nov 12, 2018)
17-45439373-G-A			Benign (Nov 12, 2018)
17-45439481-C-A		not specified	Uncertain significance (Oct 26, 2021)
17-45439481-CTG-C		Osteopetrosis, autosomal dominant 3	Pathogenic (Sep 04, 2018)
17-45439514-C-T		not specified	Uncertain significance (Jan 10, 2022)
17-45439623-C-T		Increased bone mineral density	Benign (Jun 10, 2021)
17-45439688-G-A			Benign (Nov 12, 2018)
17-45439886-T-C			Benign (Jun 19, 2021)
17-45440366-C-T			Benign (Jun 19, 2021)
17-45445409-TTGTG-T			Benign (Nov 12, 2018)
17-45445492-C-T		not specified	Uncertain significance (Dec 19, 2023)
17-45445630-T-C		not specified	Uncertain significance (Mar 24, 2023)
17-45450619-G-A			Likely benign (Nov 01, 2022)
17-45450619-G-T		not specified	Uncertain significance (Jul 19, 2023)
17-45450622-C-T		not specified	Uncertain significance (Oct 13, 2023)
17-45450749-T-C		not specified	Uncertain significance (Dec 09, 2023)
17-45453184-G-A			Benign (Nov 12, 2018)
17-45453382-G-A		not specified	Uncertain significance (Jan 23, 2024)
17-45453472-C-A		not specified	Uncertain significance (Feb 16, 2023)
17-45453505-C-T		not specified	Uncertain significance (Dec 15, 2022)

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