SNX10

protein-coding

sorting nexin 10, the group of Sorting nexins

Gene summary

This gene encodes a member of the sorting nexin family. Members of this family contain a phox (PX) domain, which is a phosphoinositide binding domain, and are involved in intracellular trafficking. This protein does not contain a coiled coil region, like some family members. This gene may play a role in regulating endosome homeostasis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2010]

MANE transcript

NM_013322.3

Inheritance

ClinVar variants

P:22U:59B:29

Top phenotype

Osteopetrosis, autosomal recessive 8

gnomAD constraint

pLI —, LoF o/e 1.07

Max pathogenic AF

—

Genomic locus

chr7:26,291,862-26,374,383

External References & Databases

Ensembl (ENSG00000086300)

Transcript & Mutation Effects

hg38 • Region Span ~82.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive osteopetrosis 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014040

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive osteopetrosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019026

Submitter: Orphanet

autosomal recessive osteopetrosis 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014040

Submitter: Genomics England PanelApp

autosomal recessive osteopetrosis 8DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014040

Submitter: ClinGen

*SNX10* was first reported in relation to autosomal recessive osteopetrosis 8 in 2012 (Aker et al., PMID: 22499339). Osteopetrosis is a metabolic bone disease characterized by increased bone density due to impaired bone resorption. The autosomal recessive form manifests in the first months of life with characteristic facial appearance, choanal stenosis, compression of cranial nerves (leading frequently to blindness, rarely to deafness and facial palsy), bone marrow insufficiency, hepatosplenomegaly, dental anomalies, and hypocalcaemia. Eighteen unique variants (missense, nonsense, frameshift, splice-site, and gross deletions) that have been reported in 24 probands in 11 publications (PMIDs: 22499339, 23123320, 23280965, 27391121, 27187610, 29090071, 29620724, 30977576, 33678645, 36526684, 36703223) are included in this curation. The maximum score for genetic evidence has been reached (12 pts). All except one proband had a homozygous variant in the *SNX10* gene. This gene-disease relationship is supported by biochemical function study, expression data, functional alteration data, and two mouse models (PMIDs: 22174188, 25212774, 28592808, 25811986, 32278070). In summary, there is definitive evidence to support the relationship between *SNX10* and autosomal recessive osteopetrosis 8. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date June 24, 2024 (SOP Version 10).

autosomal recessive osteopetrosis 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014040

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Osteopetrosis, autosomal recessive 8AR

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Dental; Hematologic; Musculoskeletal; Ophthalmologic

Intervention: Musculoskeletal

Rationale: The condition has been described as manifesting with sequelae of osteopetrosis, including failure to thrive related to upper airway issues, as well as complications affecting multiple organ systems, and successful BMT in early childhood has been described

Refs: 22499339; 23123320

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SNX10 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 138

Inborn genetic diseasesTotal: 20

not specifiedTotal: 12

Autosomal recessive osteopetrosis 8Total: 12

SNX10-related disorderTotal: 9

OsteopetrosisTotal: 1

Infantile osteopetrosisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_013322.3. 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				27 clinvar	1 clinvar	28
missense	1 clinvar	1 clinvar	57 clinvar	1 clinvar		60
nonsense	7 clinvar	4 clinvar	1 clinvar			12
start loss						0
frameshift	1 clinvar	2 clinvar				3
splice donor/acceptor (+/-2bp)	1 clinvar	5 clinvar	1 clinvar			7
Total	10	12	59	28	1	110

Highest pathogenic variant AF is 0.00004327202

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 72 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_013322.3	RefSeq	NP_037454.2	6	MANE Select
ENST00000338523.9	Ensembl	ENSP00000343709.5	6	MANE Select
NM_001199835.1	RefSeq	NP_001186764.1	6	Standard
NM_001199837.3	RefSeq	NP_001186766.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
snx10a	Danio rerio	Structure: whole organism Quality: decreased length abnormal

Gene / Model

Organism

Observed Phenotype

snx10a

Danio rerio

Structure: whole organism

Quality: decreased length

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

gastric acid secretion
endocytosis
endosome organization
protein transport
bone mineralization

Molecular Function

protein binding
1-phosphatidylinositol binding
ATPase binding

Cellular Component

nucleus
endoplasmic reticulum
centrosome
secretory granule
extrinsic component of endosome membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000338523
Coding exons: 6
Length: 82409
Individuals with no LoFs: 125699
Homozygous LoFs: 0
Heterozygous LoFs: 47
Defined: 125746
p: 0.000187

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.547	95	111	0.854	0.00000588	1346
Missense (PolyPhen)		29	39.989	0.72519		436
Synonymous	0.541	35	39.3	0.890	0.00000219	340
Loss of Function	-0.249	14	13.0	1.07	7.16e-7	143

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00027	0.00027	rare
Finnish	0.00014	0.000092	rare
European (Non-Finnish)	0.00032	0.00032	rare
South Asian	0	0.0	absent
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable phosphoinositide-binding protein involved in protein sorting and membrane trafficking in endosomes. Plays a role in cilium biogenesis through regulation of the transport and the localization of proteins to the cilium. Required for the localization to the cilium of V-ATPase subunit ATP6V1D and ATP6V0D1, and RAB8A. Involved in osteoclast differentiation and therefore bone resorption. {ECO:0000269|PubMed:17012226, ECO:0000269|PubMed:21844891, ECO:0000269|PubMed:22499339}.;
Disease: DISEASE: Osteopetrosis, autosomal recessive 8 (OPTB8) [MIM:615085]: 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. OPTB8 is clinically characterized by dense bones with no distinction between outer and inner plates, due to extensive encroachment of cortical bone into the medullary space, increased head circumference, broad open fontanelle, frontal bossing, and hepatosplenomegaly. Osteoclasts number is low and their bone resorptive capacity is impaired. {ECO:0000269|PubMed:22499339, ECO:0000269|PubMed:23123320, ECO:0000269|PubMed:23280965}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.113

Intolerance Scores

LoFtool: 0.579
RVIS EVS: -0.1
RVIS percentile EVS: 46.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.209

Gene Damage Prediction

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