MSR1

protein-coding

macrophage scavenger receptor 1, the group of CD molecules|Scavenger receptor cysteine rich domain containing|Scavenger receptors

Gene summary

This gene encodes the class A macrophage scavenger receptors, which include three different types (1, 2, 3) generated by alternative splicing of this gene. These receptors or isoforms are macrophage-specific trimeric integral membrane glycoproteins and have been implicated in many macrophage-associated physiological and pathological processes including atherosclerosis, Alzheimer's disease, and host defense. The isoforms type 1 and type 2 are functional receptors and are able to mediate the endocytosis of modified low density lipoproteins (LDLs). The isoform type 3 does not internalize modified LDL (acetyl-LDL) despite having the domain shown to mediate this function in the types 1 and 2 isoforms. It has an altered intracellular processing and is trapped within the endoplasmic reticulum, making it unable to perform endocytosis. The isoform type 3 can inhibit the function of isoforms type 1 and type 2 when co-expressed, indicating a dominant negative effect and suggesting a mechanism for regulation of scavenger receptor activity in macrophages. [provided by RefSeq, Jul 2008]

MANE transcript

NM_138715.3

Inheritance

ClinVar variants

P:9U:81B:22

Top phenotype

Barrett esophagus/esophageal adenocarcinoma; Prostate cancer

gnomAD constraint

pLI —, LoF o/e 1.24

Max pathogenic AF

—

Genomic locus

chr8:16,107,878-16,567,490

External References & Databases

Ensembl (ENSG00000038945)

Transcript & Mutation Effects

hg38 • Region Span ~459.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Barrett esophagusLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013662

Submitter: PanelApp Australia

Barrett esophagusLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0013662

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Clinical Genomic Database (CGD)

Barrett esophagus/esophageal adenocarcinoma; Prostate cancerAD

Manifestation: Gastrointestinal; Oncologic

Intervention: Gastrointestinal; Oncologic

Rationale: Awareness of disease risk may allow surveillance, preventive measures (eg, related to Barrett esophagus) and early treatment of malignancy, which may reduce morbidity and mortality

Comments: While some (eg, common) variants may increase the risk of prostate cancer slightly, others appear to confer much higher risk

Refs: 11443539; 12244320; 12839931; 12958598; 15536476; 16287155; 17768178; 17903305; 18398045; 20086112; 21791690

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MSR1 variants in ClinVar

10 Conditions Cataloged

not specifiedTotal: 91

not providedTotal: 18

MSR1-related disorderTotal: 11

Ovarian cancerTotal: 8

Barrett esophagusTotal: 3

Prostate cancerTotal: 2

Carcinoma of esophagusTotal: 2

BARRETT ESOPHAGUS/ESOPHAGEAL ADENOCARCINOMATotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_138715.3. 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				6 clinvar	5 clinvar	11
missense	1 clinvar	5 clinvar	76 clinvar	5 clinvar	4 clinvar	91
nonsense		1 clinvar		1 clinvar		2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	5 clinvar	1 clinvar		8
Total	2	7	81	13	9	112

Highest pathogenic variant AF is 0.000033504497

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_138715.3	RefSeq	NP_619729.1	9	MANE Select
ENST00000262101.10	Ensembl	ENSP00000262101.5	9	MANE Select
NM_001363744.1	RefSeq	NP_001350673.1	10	Standard
NM_002445.4	RefSeq	NP_002436.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Phagosome - Homo sapiens (human)
AGE-RAGE pathway
Vesicle-mediated transport
Binding and Uptake of Ligands by Scavenger Receptors
Scavenging by Class A Receptors

Biological Process

receptor-mediated endocytosis
phagocytosis, engulfment
negative regulation of gene expression
positive regulation of macrophage derived foam cell differentiation
positive regulation of cholesterol storage

Molecular Function

amyloid-beta binding
scavenger receptor activity
protein binding
low-density lipoprotein particle binding

Cellular Component

collagen trimer
plasma membrane
integral component of plasma membrane
integral component of membrane
endocytic vesicle membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262101
Coding exons: 9
Length: 459613
Individuals with no LoFs: 125632
Homozygous LoFs: 0
Heterozygous LoFs: 116
Defined: 125748
p: 0.000461

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-2.07	341	249	1.37	0.0000134	2955
Missense (PolyPhen)		99	75.614	1.3093		944
Synonymous	-1.43	105	87.9	1.19	0.00000497	838
Loss of Function	-1.05	27	21.7	1.24	0.00000105	254

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0020	0.0020	notable
Latino/Admixed American	0.0010	0.0010	notable
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.000094	0.000092	rare
European (Non-Finnish)	0.00028	0.00028	rare
South Asian	0.00010	0.000098	rare
Other	0.00098	0.00098	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Membrane glycoproteins implicated in the pathologic deposition of cholesterol in arterial walls during atherogenesis. Two types of receptor subunits exist. These receptors mediate the endocytosis of a diverse group of macromolecules, including modified low density lipoproteins (LDL) (PubMed:2251254). Isoform III does not internalize acetylated LDL (PubMed:9548586). {ECO:0000269|PubMed:2251254, ECO:0000269|PubMed:9548586}.;
Disease: DISEASE: Barrett esophagus (BE) [MIM:614266]: A condition characterized by a metaplastic change in which normal esophageal squamous epithelium is replaced by a columnar and intestinal-type epithelium. Patients with Barrett esophagus have an increased risk of esophageal adenocarcinoma. The main cause of Barrett esophagus is gastroesophageal reflux. The retrograde movement of acid and bile salts from the stomach into the esophagus causes prolonged injury to the esophageal epithelium and induces chronic esophagitis, which in turn is believed to trigger the pathologic changes. {ECO:0000269|PubMed:21791690}. Note=The disease may be caused by mutations affecting the gene represented in this entry. Genetic variants in MSR1 have been found in individuals with Barrett esophagus and are thought to contribute to disease susceptibility.;

Recessive Scores

pRec: 0.0964

Intolerance Scores

LoFtool: 0.106
RVIS EVS: 0
RVIS percentile EVS: 54.03

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.778

Gene Damage Prediction

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