SORCS3

protein-coding

sortilin related VPS10 domain containing receptor 3

Gene summary

This gene encodes a type-I receptor transmembrane protein that is a member of the vacuolar protein sorting 10 receptor family. Proteins of this family are defined by a vacuolar protein sorting 10 domain at the N-terminus. The N-terminal segment of this domain has a consensus motif for proprotein convertase processing, and the C-terminal segment of this domain is characterized by ten conserved cysteine residues. The vacuolar protein sorting 10 domain is followed by a leucine-rich segment, a transmembrane domain, and a short C-terminal cytoplasmic domain that interacts with adaptor molecules. The transcript is expressed at high levels in the brain, and candidate gene studies suggest that genetic variation in this gene is associated with Alzheimer's disease. Consistent with this observation, knockdown of the gene in cell culture results in an increase in amyloid precursor protein processing. [provided by RefSeq, Dec 2014]

MANE transcript

NM_014978.3

Inheritance

ClinVar variants

U:175B:18

Top phenotype

SORCS3-related disorder

gnomAD constraint

pLI —, LoF o/e 0.32

Max pathogenic AF

—

Genomic locus

chr10:104,641,290-105,265,242

External References & Databases

Ensembl (ENSG00000156395)

Transcript & Mutation Effects

hg38 • Region Span ~624.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SORCS3 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 176

not providedTotal: 13

SORCS3-related disorderTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014978.3. 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				4 clinvar	4 clinvar	8
missense			175 clinvar	6 clinvar	4 clinvar	185
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	175	10	8	193

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014978.3	RefSeq	NP_055793.1	27	MANE Select
ENST00000369701.8	Ensembl	ENSP00000358715.3	27	MANE Select
ENST00000393176.2	Ensembl	ENSP00000376876.2	5	Standard
XM_011539542.2	RefSeq	XP_011537844.1	22	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

neuropeptide signaling pathway
learning
memory
regulation of long-term synaptic depression

Molecular Function

neuropeptide receptor activity

Cellular Component

membrane
glutamatergic synapse
integral component of postsynaptic density membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000369701
Coding exons: 27
Length: 624135
Individuals with no LoFs: 125713
Homozygous LoFs: 0
Heterozygous LoFs: 35
Defined: 125748
p: 0.000139

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.52	542	651	0.832	0.0000345	7925
Missense (PolyPhen)		119	191.75	0.62061		2386
Synonymous	-0.147	263	260	1.01	0.0000148	2423
Loss of Function	4.98	20	62.5	0.320	0.00000300	741

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00017	0.00017	rare
South Asian	0.00010	0.000098	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.108

Intolerance Scores

LoFtool: 0.531
RVIS EVS: -1.17
RVIS percentile EVS: 6.04

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.276

Gene Damage Prediction

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