SNX27

protein-coding

sorting nexin 27, the group of Sorting nexins|PDZ domain containing

Gene summary

This gene encodes a member of the sorting nexin family, a diverse group of cytoplasmic and membrane-associated proteins involved in endocytosis of plasma membrane receptors and protein trafficking through these compartments. All members of this protein family contain a phosphoinositide binding domain (PX domain). A highly similar protein in mouse is responsible for the specific recruitment of an isoform of serotonin 5-hydroxytryptamine 4 receptor into early endosomes, suggesting the analogous role for the human protein. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001330723.2

Inheritance

ClinVar variants

P:23U:186B:145

Top phenotype

neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr1:151,612,006-151,699,091

External References & Databases

Ensembl (ENSG00000143376)

Transcript & Mutation Effects

hg38 • Region Span ~87.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: LiferaOmics

Genetic evidence – Published PMID: 25894286 – Family 1 – one proband (four affected siblings reported). Case-level (biallelic predicted null in AR model; homozygous frameshift; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation (multiple affected sibs with consistent genotype; conservative assignment) = 0.5 Case-control = 0 Family 1 total = 1.5 PMID: 31721175 – Family 2 – one proband. Case-level (AR compound heterozygous; one truncating + one non-LOF ; each variant evaluated independently; no consanguinity deduction applied) = 1.6; Segregation = 0 Case-control = 0 Family 2 total = 1.6 PMID: 31721175 – Family 3 – one proband. Case-level (AR compound heterozygous; one truncating + one non-LOF ; each variant evaluated independently; no consanguinity deduction applied) = 1.6; Segregation = 0 Case-control = 0 Family 3 total = 1.6 Published genetic evidence total = 1.5 + 1.6 + 1.6 = 4.7 / 12 Genetic evidence – Our cases Family 1 – One proband. Case-level (pLOF; homozygous; consanguinity −0.5 applied) = (1.5− 0.5) = 1.0; Segregation = 0; Case-control = 0 Case-control = 0 Family 1 total = 1.0 Family 2 – One proband. Case-level (pLOF; homozygous; consanguinity −0.5 applied) = (1.5− 0.5) = 1.0; Segregation = 0; Case-control = 0 Family 2 total = 1.0 Family 3 – One proband. Case-level (pLOF; homozygous; no-consanguinity) = 1.5; Segregation = 0; Case-control = 0; Segregation = 0 Case-control = 0 Family 3 total = 1.5 Our genetic evidence total = 1.0 + 1.0+ 1.5 = 3.5 / 12 Total genetic evidence (published AR + our cases) 4.7 (published AR) + 3.5 (our cases) = 8.2 / 12 Experimental evidence – Published PMID: 25894286 – Patient fibroblasts demonstrate absence of SNX27 protein, supporting pathogenic loss of function. Functional alteration (patient-derived cells) = 1.0 PMID: 21300787 – Snx27 deficiency in mice results in growth retardation and implicates NMDA receptor trafficking defects. Non-human model (supportive, not full phenotypic recapitulation) = 0.5 PMID: 23524343 – Loss of SNX27 disrupts glutamate receptor recycling and causes excitatory synaptic dysfunction. Gene function / biological plausibility = 0.5 Experimental evidence total = 2.0 / 6 Overall score Genetic evidence = 8.2 Experimental evidence = 2.0 Overall score = 10.2 / 18

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SNX27 variants in ClinVar

7 Conditions Cataloged

Severe myoclonic epilepsy in infancyTotal: 419

Inborn genetic diseasesTotal: 55

not providedTotal: 15

SNX27-related disorderTotal: 10

DAMSEH-DANSON NEURODEVELOPMENTAL DISORDERTotal: 7

not specifiedTotal: 2

See casesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001330723.2. 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	137 clinvar	2 clinvar	142
missense	2 clinvar	1 clinvar	177 clinvar	6 clinvar		186
nonsense	8 clinvar	1 clinvar	1 clinvar			10
start loss						0
frameshift	8 clinvar	2 clinvar	1 clinvar			11
splice donor/acceptor (+/-2bp)		1 clinvar	4 clinvar			5
Total	18	5	186	143	2	354

Highest pathogenic variant AF is 0.000023170871

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001330723.2	RefSeq	NP_001317652.1	12	MANE Select
ENST00000458013.7	Ensembl	ENSP00000400333.2	12	MANE Select
NM_001437601.1	RefSeq	NP_001424530.1	11	Standard
NM_001437602.1	RefSeq	NP_001424531.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

establishment of natural killer cell polarity
intracellular protein transport
signal transduction
endosome to lysosome transport
endosomal transport

Molecular Function

protein binding
phosphatidylinositol-3-phosphate binding
phosphatidylinositol binding

Cellular Component

immunological synapse
nucleoplasm
endosome
early endosome
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000368843
Coding exons: 12
Length: 87027
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125748
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.17	179	282	0.636	0.0000152	3433
Missense (PolyPhen)		67	114.26	0.58636		1337
Synonymous	1.58	92	113	0.811	0.00000666	996
Loss of Function	4.98	2	32.8	0.0610	0.00000205	345

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.00023	0.00023	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the retrograde transport from endosome to plasma membrane, a trafficking pathway that promotes the recycling of internalized transmembrane proteins. Following internalization, endocytosed transmembrane proteins are delivered to early endosomes and recycled to the plasma membrane instead of being degraded in lysosomes. SNX27 specifically binds and directs sorting of a subset of transmembrane proteins containing a PDZ- binding motif at the C-terminus: following interaction with target transmembrane proteins, associates with the retromer complex, preventing entry into the lysosomal pathway, and promotes retromer-tubule based plasma membrane recycling. SNX27 also binds with the WASH complex. Interacts with membranes containing phosphatidylinositol-3-phosphate (PtdIns(3P)). May participate in establishment of natural killer cell polarity. Recruits CYTIP to early endosomes. {ECO:0000269|PubMed:17351151, ECO:0000269|PubMed:20733053, ECO:0000269|PubMed:21300787, ECO:0000269|PubMed:21303929, ECO:0000269|PubMed:21602791, ECO:0000269|PubMed:21926430, ECO:0000269|PubMed:22411990, ECO:0000269|PubMed:23563491}.;

Recessive Scores

pRec: 0.0851

Intolerance Scores

LoFtool: 0.118
RVIS EVS: 0.06
RVIS percentile EVS: 58.53

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.890

Gene Damage Prediction

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