SNX14

protein-coding

sorting nexin 14, the group of Sorting nexins

Gene summary

This gene encodes a member of the sorting nexin family. Members of this family have a phox (PX) phosphoinositide binding domain and are involved in intracellular trafficking. The encoded protein also contains a regulator of G protein signaling (RGS) domain. Regulator of G protein signaling family members are regulatory molecules that act as GTPase activating proteins for G alpha subunits of heterotrimeric G proteins. Alternate splicing results in transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]

MANE transcript

NM_153816.6

Inheritance

ClinVar variants

P:51U:173B:54

Top phenotype

Spinocerebellar ataxia, autosomal recessive 20

gnomAD constraint

pLI —, LoF o/e 0.62

Max pathogenic AF

—

Genomic locus

chr6:85,504,776-85,594,156

External References & Databases

Ensembl (ENSG00000135317)

Transcript & Mutation Effects

hg38 • Region Span ~89.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive spinocerebellar ataxia 20STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014601

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive spinocerebellar ataxia 20DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014601

Submitter: ClinGen

Sorting nexin 14 (*SNX14*) was first reported in relation to autosomal recessive spinocerebellar ataxia 20 (SCAR20) in 2014 (Thomas et al., PMID: 25439728). SCAR20 is a pediatric onset disease which often involves ataxia, cerebellar atrophy, coarse facial features and intellectual disability (PMIDs 25439728, 25848753). Six variants (two stop-gain, one frame shift, one missense, one canonical splice, and one deep intronic) that have been reported in six probands in four publications (PMIDs: 25439728, 25848753, 27913285, 37485342) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by animal models, cell culture models, and biochemical data (PMIDs 33310904, 38625743, 29635513). The effects from a loss of function or expression was shown to be more pronounced in cerebral tissue and that disruption to lipid homeostasis is likely involved in pathogenesis. In summary, there is definitive evidence supporting the relationship between *SNX14* and autosomal recessive spinocerebellar ataxia 20. 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 Cerebellar Ataxia GCEP on the meeting date October 9, 2024 (SOP Version 11).

autosomal recessive spinocerebellar ataxia 20STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014601

Submitter: Ambry Genetics

autosomal recessive spinocerebellar ataxia 20SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014601

Submitter: Orphanet

autosomal recessive spinocerebellar ataxia 20STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014601

Submitter: PanelApp Australia

autosomal recessive spinocerebellar ataxia 20DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014601

Submitter: G2P

Clinical Genomic Database (CGD)

Spinocerebellar ataxia, autosomal recessive 20AR

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: 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

Refs: 24501761; 25439728; 25848753

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SNX14 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 223

Inborn genetic diseasesTotal: 109

Autosomal recessive spinocerebellar ataxia 20Total: 53

SNX14-related disorderTotal: 22

not specifiedTotal: 21

Neurodevelopmental disorderTotal: 2

Cerebellar ataxiaTotal: 1

Spinocerebellar atrophyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_153816.6. 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			3 clinvar	46 clinvar	2 clinvar	51
missense	1 clinvar		158 clinvar	5 clinvar	1 clinvar	165
nonsense	4 clinvar	12 clinvar				16
start loss						0
frameshift	8 clinvar	9 clinvar				17
splice donor/acceptor (+/-2bp)	4 clinvar	13 clinvar	12 clinvar			29
Total	17	34	173	51	3	278

Highest pathogenic variant AF is 0.000047786907

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 228 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_153816.6	RefSeq	NP_722523.1	29	MANE Select
ENST00000314673.8	Ensembl	ENSP00000313121.3	29	MANE Select
NM_001297614.3	RefSeq	NP_001284543.1	28	Standard
NM_001304479.2	RefSeq	NP_001291408.1	28	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
snx14	Danio rerio	Structure: neuron Quality: apoptotic abnormal

Gene / Model

Organism

Observed Phenotype

snx14

Danio rerio

Structure: neuron

Quality: apoptotic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein transport
autophagosome maturation

Molecular Function

phosphatidylinositol-3,5-bisphosphate binding

Cellular Component

lysosome
lysosomal membrane
late endosome
integral component of membrane
dendrite

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000314673
Coding exons: 29
Length: 88661
Individuals with no LoFs: 125650
Homozygous LoFs: 0
Heterozygous LoFs: 98
Defined: 125748
p: 0.000390

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.85	350	462	0.758	0.0000218	6215
Missense (PolyPhen)		87	141.32	0.61564		1963
Synonymous	-0.719	169	158	1.07	0.00000731	1692
Loss of Function	2.61	35	56.1	0.624	0.00000270	748

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00038	0.00037	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.0012	0.0011	notable
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00044	0.00042	rare
South Asian	0.00040	0.00039	rare
Other	0.00034	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in maintaining normal neuronal excitability and synaptic transmission. May be involved in several stages of intracellular trafficking (By similarity). Required for autophagosome clearance, possibly by mediating the fusion of lysosomes with autophagosomes (Probable). Binds phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2), a key component of late endosomes/lysosomes (PubMed:25848753). Does not bind phosphatidylinositol 3-phosphate (PtdIns(3P)) (PubMed:25848753, PubMed:25148684). {ECO:0000250|UniProtKB:Q8BHY8, ECO:0000269|PubMed:25148684, ECO:0000269|PubMed:25848753, ECO:0000305|PubMed:25848753}.;

Recessive Scores

pRec: 0.108

Intolerance Scores

LoFtool: 0.964
RVIS EVS: -0.49
RVIS percentile EVS: 22.65

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.508

Gene Damage Prediction

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