LAMTOR2

protein-coding

late endosomal/lysosomal adaptor, MAPK and MTOR activator 2, the group of Ragulator complex

Gene summary

The product of this gene is highly conserved with a mouse protein associated with the cytoplasmic face of late endosomes and lysosomes. The mouse protein interacts with MAPK scaffold protein 1, a component of the mitogen-activated protein kinase pathway. In humans, a mutation in this gene has been associated with a primary immunodeficiency syndrome, and suggests a role for this protein in endosomal biogenesis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2009]

Previous symbols:

ROBLD3

MANE transcript

NM_014017.4

Inheritance

ClinVar variants

U:43B:26

Top phenotype

Immunodeficiency due to defect in MAPBP-interacting protein

gnomAD constraint

pLI —, LoF o/e 0.3

Max pathogenic AF

—

Genomic locus

chr1:156,054,782-156,058,506

External References & Databases

Ensembl (ENSG00000116586)

Transcript & Mutation Effects

hg38 • Region Span ~3.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

primary immunodeficiency syndrome due to p14 deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012559

Submitter: PanelApp Australia

primary immunodeficiency syndrome due to p14 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012559

Submitter: Orphanet

primary immunodeficiency syndrome due to p14 deficiencyLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0012559

Submitter: Labcorp Genetics (formerly Invitae)

primary immunodeficiency syndrome due to p14 deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0012559

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Immunodeficiency due to defect in MAPBP-interacting proteinAR

Manifestation: Allergy/Immunology/Infectious; Dermatologic; Musculoskeletal

Intervention: Allergy/Immunology/Infectious

Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial (severe congenital neutropenia has been reported as responding to G-CSF)

Refs: 17195838

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LAMTOR2 variants in ClinVar

4 Conditions Cataloged

not providedTotal: 76

not specifiedTotal: 12

Primary immunodeficiency syndrome due to p14 deficiencyTotal: 2

LAMTOR2-related disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014017.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	26 clinvar		28
missense			34 clinvar			34
nonsense			3 clinvar			3
start loss						0
frameshift			4 clinvar			4
splice donor/acceptor (+/-2bp)						0
Total	0	0	43	26	0	69

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014017.4	RefSeq	NP_054736.1	4	MANE Select
ENST00000368305.9	Ensembl	ENSP00000357288.4	4	MANE Select
NM_001145264.2	RefSeq	NP_001138736.1	3	Standard
ENST00000368302.3	Ensembl	ENSP00000357285.3	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

mTOR signaling pathway - Homo sapiens (human)
MAP2K and MAPK activation
Neutrophil degranulation
Signal Transduction
Gene expression (Transcription)

Biological Process

MAPK cascade
activation of MAPKK activity
regulation of cell growth
cell cycle arrest
regulation of macroautophagy

Molecular Function

guanyl-nucleotide exchange factor activity
protein binding
protein-containing complex scaffold activity

Cellular Component

lysosomal membrane
late endosome
plasma membrane
endosome membrane
specific granule membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000368305
Coding exons: 4
Length: 3759
Individuals with no LoFs: 125744
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125748
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.26	40	69.7	0.574	0.00000364	800
Missense (PolyPhen)		5	16.435	0.30422		215
Synonymous	-0.448	31	28.0	1.11	0.00000154	259
Loss of Function	1.70	2	6.77	0.295	3.79e-7	69

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. Adapter protein that enhances the efficiency of the MAP kinase cascade facilitating the activation of MAPK2. {ECO:0000269|PubMed:20381137, ECO:0000269|PubMed:22980980}.;
Disease: DISEASE: Immunodeficiency due to defect in MAPBP-interacting protein (ID-MAPBPIP) [MIM:610798]: This form of primary immunodeficiency syndrome includes congenital neutropenia, partial albinism, short stature and B-cell and cytotoxic T-cell deficiency. {ECO:0000269|PubMed:17195838}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0827

Intolerance Scores

RVIS EVS: 0.04
RVIS percentile EVS: 56.25

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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