SPART

protein-coding

spartin

Gene summary

This gene encodes a protein containing a MIT (Microtubule Interacting and Trafficking molecule) domain, and is implicated in regulating endosomal trafficking and mitochondria function. The protein localizes to mitochondria and partially co-localizes with microtubules. Stimulation with epidermal growth factor (EGF) results in protein translocation to the plasma membrane, and the protein functions in the degradation and intracellular trafficking of EGF receptor. Multiple alternatively spliced variants, encoding the same protein, have been identified. Mutations associated with this gene cause autosomal recessive spastic paraplegia 20 (Troyer syndrome). [provided by RefSeq, Nov 2008]

Previous symbols:

SPG20

MANE transcript

NM_015087.5

Inheritance

ClinVar variants

P:33U:197B:91

Top phenotype

Spastic paraplegia 20, autosomal recessive (Troyer syndrome)

gnomAD constraint

pLI —, LoF o/e 0.54

Max pathogenic AF

—

Genomic locus

chr13:36,301,638-36,370,180

External References & Databases

Ensembl (ENSG00000133104)

Transcript & Mutation Effects

hg38 • Region Span ~68.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Troyer syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010156

Submitter: ClinGen

*SPART* was first reported in relation to Troyer Syndrome in 2002 in the Old Order Amish population (PMIDs:6022528, 12134148). Troyer Syndrome is an autosomal recessive form of complicated spastic paraplegia, typically with onset between the ages of 1-2 years. Affected individuals present with short stature, distal amyotrophy, dysarthria, and mild cognitive defects (Patel et al., PMID:12134148). At least 7 unique variants have been reported in 70 individuals, including one founder mutation (PMIDs: 12134148, 20437587, 31314595, 27539578). The molecular mechanism appears to be loss of function. Experimentally, the gene-disease relationship is supported by biochemical assays, in vitro studies, a mouse model that partially recapitulates the human phenotype (PMID:19307600, PMID: 20719964), and rescue experiments in C. elegans (PMID: 26114733). In summary, there is definitive evidence to support the relationship between SPART and autosomal recessive Troyer Syndrome. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. The Cerebral Palsy Expert panel approved the classification on December 19, 2022 (SOP version 9).

Troyer syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010156

Submitter: Orphanet

Clinical Genomic Database (CGD)

Spastic paraplegia 20, autosomal recessive (Troyer syndrome)AR

Manifestation: Craniofacial; Musculoskeletal; 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: 6022528; 12134148; 18413476; 20437587; 26003402

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SPART variants in ClinVar

15 Conditions Cataloged

not providedTotal: 260

Inborn genetic diseasesTotal: 103

Troyer syndromeTotal: 53

Hereditary spastic paraplegiaTotal: 17

SPART-related disorderTotal: 14

not specifiedTotal: 11

Neurodevelopmental delayTotal: 3

EpilepsyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015087.5. 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			5 clinvar	77 clinvar	1 clinvar	83
missense		2 clinvar	183 clinvar	13 clinvar		198
nonsense	3 clinvar	5 clinvar	1 clinvar			9
start loss						0
frameshift	12 clinvar	8 clinvar	3 clinvar			23
splice donor/acceptor (+/-2bp)		3 clinvar	5 clinvar			8
Total	15	18	197	90	1	321

Highest pathogenic variant AF is 0.000052055446

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 138 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015087.5	RefSeq	NP_055902.1	8	MANE Select
ENST00000438666.7	Ensembl	ENSP00000406061.2	8	MANE Select
NM_001142294.2	RefSeq	NP_001135766.1	8	Standard
NM_001142295.2	RefSeq	NP_001135767.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Endocytosis - Homo sapiens (human)
EGFR1

Biological Process

abscission
negative regulation of BMP signaling pathway
lipid droplet organization
negative regulation of collateral sprouting in absence of injury
neuromuscular process

Molecular Function

protein binding
ubiquitin protein ligase binding

Cellular Component

cytoplasm
mitochondrial outer membrane
lipid droplet
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000451493
Coding exons: 8
Length: 68543
Individuals with no LoFs: 125687
Homozygous LoFs: 0
Heterozygous LoFs: 61
Defined: 125748
p: 0.000243

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0699	346	350	0.989	0.0000181	4325
Missense (PolyPhen)		84	87.117	0.96423		1055
Synonymous	0.0128	130	130	0.999	0.00000719	1320
Loss of Function	2.22	15	27.5	0.545	0.00000132	355

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00027	0.00027	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00023	0.00023	rare
South Asian	0.00036	0.00036	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be implicated in endosomal trafficking, or microtubule dynamics, or both. Participates in cytokinesis (PubMed:20719964). {ECO:0000269|PubMed:20719964}.;
Disease: DISEASE: Spastic paraplegia 20, autosomal recessive (SPG20) [MIM:275900]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG20 is characterized by dysarthria, distal amyotrophy, mild developmental delay and short stature. {ECO:0000269|PubMed:12134148, ECO:0000269|PubMed:27539578, ECO:0000269|PubMed:28875386}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.108

Intolerance Scores

RVIS EVS: -0.49
RVIS percentile EVS: 22.7

Essentials

Essential (gene trap): N