LRSAM1

leucine rich repeat and sterile alpha motif containing 1, the group of Sterile alpha motif domain containing|Ring finger proteins

Basic information

Region (hg38): 9:127451489-127503499

Links

ENSG00000148356 ∙ NCBI:90678 ∙ OMIM:610933 ∙ HGNC:25135 ∙ Uniprot:Q6UWE0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Charcot-Marie-Tooth disease axonal type 2P (Supportive), mode of inheritance: AD
• Charcot-Marie-Tooth disease axonal type 2P (Strong), mode of inheritance: AR
• Charcot-Marie-Tooth disease axonal type 2P (Strong), mode of inheritance: AD
• Charcot-Marie-Tooth disease axonal type 2P (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Charcot-Marie-Tooth disease, axonal, type 2P	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	Neurologic	20865121; 22012984; 22781092

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the LRSAM1 gene.

• Charcot-Marie-Tooth disease axonal type 2P (28 variants)
• Inborn genetic diseases (5 variants)
• Charcot-Marie-Tooth disease (4 variants)
• not provided (3 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the LRSAM1 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				134	1	135
missense	1	2	323	7	3	336
nonsense	11	11				22
start loss			1			1
frameshift	15	11				26
inframe indel	1		5			6
splice donor/acceptor (+/-2bp)	3	13	5			21
splice region			26	26	3	55
non coding			23	131	46	200
Total	31	37	357	272	50

Highest pathogenic variant AF is 0.0000329

Variants in LRSAM1

This is a list of pathogenic ClinVar variants found in the LRSAM1 region.

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

Position	Type	Phenotype	Significance	ClinVar
9-127451542-C-T		Charcot-Marie-Tooth disease axonal type 2P	Benign/Likely benign (May 13, 2021)
9-127451550-G-A		Charcot-Marie-Tooth disease axonal type 2P	Uncertain significance (Jan 12, 2018)
9-127451556-C-T		Charcot-Marie-Tooth disease axonal type 2P	Uncertain significance (Jan 13, 2018)
9-127451659-A-G		Charcot-Marie-Tooth disease axonal type 2P • not specified	Conflicting classifications of pathogenicity (Jan 12, 2018)
9-127451716-C-T		Charcot-Marie-Tooth disease axonal type 2P	Uncertain significance (Jan 12, 2018)
9-127451779-G-A		Charcot-Marie-Tooth disease axonal type 2P	Uncertain significance (Jan 13, 2018)
9-127451784-CTTG-C		Charcot-Marie-Tooth disease type 2	Uncertain significance (Jun 14, 2016)
9-127451796-A-G		Charcot-Marie-Tooth disease axonal type 2P	Uncertain significance (Jan 13, 2018)
9-127451808-A-G		Charcot-Marie-Tooth disease axonal type 2P	Uncertain significance (Jan 13, 2018)
9-127451990-C-A		Charcot-Marie-Tooth disease axonal type 2P	Uncertain significance (Apr 27, 2017)
9-127452039-C-T		Charcot-Marie-Tooth disease axonal type 2P	Uncertain significance (Jan 13, 2018)
9-127452082-C-T		Charcot-Marie-Tooth disease axonal type 2P	Uncertain significance (Jan 13, 2018)
9-127452135-C-T			Benign (Jun 20, 2018)
9-127452529-G-T			Likely benign (Nov 18, 2020)
9-127454489-G-GC		Charcot-Marie-Tooth disease axonal type 2P	Uncertain significance (Nov 08, 2023)
9-127454509-G-A		not specified	Likely benign (Oct 08, 2015)
9-127454528-A-T		Charcot-Marie-Tooth disease axonal type 2P	Uncertain significance (Jan 09, 2024)
9-127454532-C-T		Charcot-Marie-Tooth disease axonal type 2P	Uncertain significance (Jan 16, 2024)
9-127454533-G-A		Charcot-Marie-Tooth disease axonal type 2P	Likely benign (May 24, 2023)
9-127454536-C-T		Charcot-Marie-Tooth disease axonal type 2P	Likely benign (Oct 15, 2020)
9-127454540-T-C		Charcot-Marie-Tooth disease axonal type 2P	Uncertain significance (Jun 23, 2022)
9-127454543-C-T		Charcot-Marie-Tooth disease axonal type 2P • Inborn genetic diseases	Uncertain significance (Oct 18, 2023)
9-127454544-G-A		Charcot-Marie-Tooth disease axonal type 2P	Uncertain significance (Jun 18, 2023)
9-127454547-A-AGCGGAAACCCAGTGAGGAGGC		Charcot-Marie-Tooth disease axonal type 2P • Inborn genetic diseases	Uncertain significance (Aug 20, 2023)
9-127454549-C-G		Charcot-Marie-Tooth disease axonal type 2P	Uncertain significance (Oct 31, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
LRSAM1	protein_coding	protein_coding	ENST00000323301	24	52016

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.10e-13	0.999	125631	0	117	125748	0.000465

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.407	399	423	0.944	0.0000283	4713
Missense in Polyphen		130	137.64	0.94448		1525
Synonymous	-0.481	180	172	1.05	0.0000115	1357
Loss of Function	3.00	29	52.4	0.553	0.00000270	573

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00181	0.00181
Ashkenazi Jewish	0.00	0.00
East Asian	0.000273	0.000272
Finnish	0.000157	0.000139
European (Non-Finnish)	0.000328	0.000325
Middle Eastern	0.000273	0.000272
South Asian	0.000196	0.000196
Other	0.00148	0.00147

dbNSFP

Source: dbNSFP

• Function: FUNCTION: E3 ubiquitin-protein ligase that mediates monoubiquitination of TSG101 at multiple sites, leading to inactivate the ability of TSG101 to sort endocytic (EGF receptors) and exocytic (HIV-1 viral proteins) cargos (PubMed:15256501). Bacterial recognition protein that defends the cytoplasm from invasive pathogens (PubMed:23245322). Localizes to several intracellular bacterial pathogens and generates the bacteria- associated ubiquitin signal leading to autophagy-mediated intracellular bacteria degradation (xenophagy) (PubMed:23245322, PubMed:25484098). {ECO:0000269|PubMed:15256501, ECO:0000269|PubMed:23245322, ECO:0000269|PubMed:25484098}.
• Disease: DISEASE: Charcot-Marie-Tooth disease 2P (CMT2P) [MIM:614436]: An axonal 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. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. {ECO:0000269|PubMed:20865121, ECO:0000269|PubMed:22012984, ECO:0000269|PubMed:27615052, ECO:0000269|PubMed:27686364}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Immune System;Adaptive Immune System;Antigen processing: Ubiquitination & Proteasome degradation;Class I MHC mediated antigen processing & presentation (Consensus)

Recessive Scores

• pRec: 0.143

Intolerance Scores

• loftool: 0.809
• rvis_EVS: -0.44
• rvis_percentile_EVS: 24.63

Haploinsufficiency Scores

• pHI: 0.386
• hipred: Y
• hipred_score: 0.683
• ghis: 0.519

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.978

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Lrsam1
• 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); normal phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: lrsam1
• Affected structure: motor neuron
• Phenotype tag: abnormal
• Phenotype quality: disorganized

Gene ontology

• Biological process: protein polyubiquitination;autophagy;protein catabolic process;negative regulation of endocytosis;viral budding;protein autoubiquitination;ubiquitin-dependent endocytosis;positive regulation of xenophagy;positive regulation of autophagosome assembly
• Cellular component: cytoplasm;cytosol;membrane
• Molecular function: ubiquitin-protein transferase activity;protein binding;metal ion binding;ubiquitin protein ligase activity