GeneBe

SPTAN1

protein-coding

spectrin alpha, non-erythrocytic 1, the group of Spectrins|EF-hand domain containing

Gene summary

Spectrins are a family of filamentous cytoskeletal proteins that function as essential scaffold proteins that stabilize the plasma membrane and organize intracellular organelles. Spectrins are composed of alpha and beta dimers that associate to form tetramers linked in a head-to-head arrangement. This gene encodes an alpha spectrin that is specifically expressed in nonerythrocytic cells. The encoded protein has been implicated in other cellular functions including DNA repair and cell cycle regulation. Mutations in this gene are the cause of early infantile epileptic encephalopathy-5. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Sep 2010]

MANE transcript

NM_001130438.3

Inheritance

AR, AD

ClinVar variants

P:148U:1275B:998

Top phenotype

Developmental and epileptic encephalopathy 5; Developmental delay with or without epilepsy; Neuronopathy, distal hereditary motor, 11, autosomal dominant; Spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr9:128,552,558-128,633,662

External References & Databases

Ensembl (ENSG00000197694)NCBI Gene (6709)OMIM (182810)HGNC:11273GenCCUniProt (Q13813)AlphaFoldClinVar (SPTAN1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~81.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary spastic paraplegiaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019064

Submitter: PanelApp Australia

genetic developmental and epileptic encephalopathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: ClinGen

**Note: In September 2021, the ClinGen Epilepsy GCEP opted to change the disease term on this curation from early-onset epileptic encephalopathy to developmental and epileptic encephalopathy. The original evidence and conclusion remains the same; therefore, the original date of approval has not been changed. **

developmental and epileptic encephalopathy, 5DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013277

Submitter: G2P

developmental and epileptic encephalopathy, 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013277

Submitter: Ambry Genetics

spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0957813

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 5DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013277

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

developmental and epileptic encephalopathy, 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013277

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy, 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013277

Submitter: PanelApp Australia

neuronopathy, distal hereditary motor, autosomal dominant 11STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0957875

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 5; Developmental delay with or without epilepsy; Neuronopathy, distal hereditary motor, 11, autosomal dominant; Spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxiaAD

Manifestation: 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

Comments: As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

Refs: 18469812; 18065176; 20493457; 22258530; 29050398; 31332438; 33206935; 33578420; 35150594; 36331550Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SPTAN1 variants in ClinVar

40 Conditions Cataloged
Early-infantile DEETotal: 2420
not providedTotal: 916
not specifiedTotal: 459
Inborn genetic diseasesTotal: 418
Developmental and epileptic encephalopathy, 5Total: 372
SPTAN1-related disorderTotal: 138
Developmental delay with or without epilepsyTotal: 40
Neuronopathy, distal hereditary motor, autosomal dominant 11Total: 35

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001130438.3. 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.

EffectPLPVUSLBBSum
synonymous
30
clinvar
728
clinvar
16
clinvar
 774
missense
8
clinvar
44
clinvar
1192
clinvar
237
clinvar
16
clinvar
 1497
nonsense
20
clinvar
19
clinvar
21
clinvar
 60
start loss
0
frameshift
19
clinvar
23
clinvar
14
clinvar
 56
splice donor/acceptor (+/-2bp)
15
clinvar
18
clinvar
1
clinvar
 34
Total471011275966322421

Highest pathogenic variant AF is 0.000011158998

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 83 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001130438.3RefSeqNP_001123910.156MANE Select
ENST00000372739.7EnsemblENSP00000361824.456MANE Select
NM_001195532.2RefSeqNP_001182461.154Standard
NM_001363759.2RefSeqNP_001350688.157Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
sptan1Danio rerio

Structure: whole organism

Quality: lethal (sensu genetics)

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Apoptosis - Homo sapiens (human)
  • Fas Ligand (FasL) pathway and Stress induction of Heat Shock Proteins (HSP) regulation
  • Developmental Biology
  • Neutrophil degranulation
  • Signal Transduction

Biological Process

  • MAPK cascade
  • endoplasmic reticulum to Golgi vesicle-mediated transport
  • cytoskeleton organization
  • axon guidance
  • neutrophil degranulation

Molecular Function

  • actin binding
  • Ras guanyl-nucleotide exchange factor activity
  • structural constituent of cytoskeleton
  • calcium ion binding
  • protein binding

Cellular Component

  • extracellular region
  • cytosol
  • spectrin
  • microtubule cytoskeleton
  • membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000372739
Coding exons
56
Length
81076
Individuals with no LoFs
125722
Homozygous LoFs
0
Heterozygous LoFs
26
Defined
125748
p
0.000103
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense5.528021.38e+30.5820.000091716469
Missense (PolyPhen)230520.810.441626284
Synonymous-1.255745371.070.00003524517
Loss of Function10.581430.05590.000007831644

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.000230.00023rare
Ashkenazi Jewish00.0absent
East Asian0.000270.00027rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000970.000097rare
South Asian0.0000330.000033rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane.;
Disease
DISEASE: Epileptic encephalopathy, early infantile, 5 (EIEE5) [MIM:613477]: A disorder characterized by seizures associated with hypsarrhythmia, profound mental retardation with lack of visual attention and speech development, as well as spastic quadriplegia. {ECO:0000269|PubMed:20493457, ECO:0000269|PubMed:27864847}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.391

Intolerance Scores

LoFtool
0.116
RVIS EVS
-3.53
RVIS percentile EVS
0.31

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.930

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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