GeneBe

SPTA1

protein-coding

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

Gene summary

This gene encodes a member of a family of molecular scaffold proteins that link the plasma membrane to the actin cytoskeleton and functions in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles. The encoded protein is primarily composed of 22 spectrin repeats which are involved in dimer formation. It forms a component of the erythrocyte plasma membrane. Mutations in this gene result in a variety of hereditary red blood cell disorders, including elliptocytosis-2, pyropoikilocytosis, and spherocytosis, type 3. [provided by RefSeq, Aug 2017]

MANE transcript

NM_003126.4

Inheritance

AR, AD

ClinVar variants

P:234U:815B:296

Top phenotype

Spherocytosis, type 3; Pyropoikilocytosis , hereditary; Ellipsocytosis 2

gnomAD constraint

pLI —, LoF o/e 0.39

Max pathogenic AF

—

Genomic locus

chr1:158,610,704-158,686,715

External References & Databases

Ensembl (ENSG00000163554)NCBI Gene (6708)OMIM (182860)HGNC:11272GenCCUniProt (P02549)AlphaFoldClinVar (SPTA1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~76.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary spherocytosis type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010053

Submitter: Ambry Genetics

pyropoikilocytosis, hereditaryMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009948

Submitter: Ambry Genetics

elliptocytosis 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007533

Submitter: PanelApp Australia

pyropoikilocytosis, hereditarySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009948

Submitter: PanelApp Australia

hereditary elliptocytosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017319

Submitter: Orphanet

hereditary spherocytosis type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010053

Submitter: PanelApp Australia

elliptocytosis 2MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007533

Submitter: Ambry Genetics

hereditary spherocytosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019350

Submitter: Orphanet

pyropoikilocytosis, hereditarySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009948

Submitter: Labcorp Genetics (formerly Invitae)

elliptocytosis 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007533

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.

hereditary spherocytosis type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010053

Submitter: Labcorp Genetics (formerly Invitae)

elliptocytosis 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007533

Submitter: Labcorp Genetics (formerly Invitae)

hereditary spherocytosis type 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010053

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.

Clinical Genomic Database (CGD)

Spherocytosis, type 3; Pyropoikilocytosis , hereditary; Ellipsocytosis 2AD/AR

Manifestation: Hematologic

Intervention: Hematologic

Rationale: Individuals have been described with severe hemolytic anemia, which has been treated by interventions such as frequent transfusions and splenectomy

Refs: 1191563; 7070419; 2987946; 3785322; 3597773; 2567189; 2794061; 1541680; 8226774; 8941647; 16150946; 21251457Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SPTA1 variants in ClinVar

21 Conditions Cataloged
not providedTotal: 1089
not specifiedTotal: 560
Elliptocytosis 2Total: 262
Hereditary spherocytosis type 3Total: 258
Pyropoikilocytosis, hereditaryTotal: 240
SPTA1-related disorderTotal: 119
Familial hemolytic anemiaTotal: 4
Hereditary spherocytosis type 1Total: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003126.4. 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
2
clinvar
28
clinvar
131
clinvar
14
clinvar
 175
missense
3
clinvar
19
clinvar
776
clinvar
144
clinvar
7
clinvar
 949
nonsense
36
clinvar
63
clinvar
3
clinvar
 102
start loss
2
clinvar
 2
frameshift
18
clinvar
45
clinvar
2
clinvar
 65
splice donor/acceptor (+/-2bp)
5
clinvar
43
clinvar
4
clinvar
 52
Total62172815275211345

Highest pathogenic variant AF is 0.006348737

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_003126.4RefSeqNP_003117.252MANE Select
ENST00000643759.2EnsemblENSP00000495214.152MANE Select
XM_011509916.3RefSeqXP_011508218.152Standard
XM_011509917.4RefSeqXP_011508219.151Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Apoptosis - Homo sapiens (human)
  • Developmental Biology
  • Signal Transduction
  • Vesicle-mediated transport
  • Membrane Trafficking

Biological Process

  • MAPK cascade
  • lymphocyte homeostasis
  • porphyrin-containing compound biosynthetic process
  • endoplasmic reticulum to Golgi vesicle-mediated transport
  • plasma membrane organization

Molecular Function

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

Cellular Component

  • cytosol
  • spectrin
  • spectrin-associated cytoskeleton
  • actin cytoskeleton
  • axon

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000368147
Coding exons
52
Length
75993
Individuals with no LoFs
124691
Homozygous LoFs
0
Heterozygous LoFs
109
Defined
124800
p
0.000437
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-2.2514561.23e+31.180.000070916002
Missense (PolyPhen)569482.031.18046693
Synonymous-2.895404611.170.00002424375
Loss of Function6.75571450.3940.000008441685

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000390.00039rare
Latino/Admixed American0.000640.00064rare
Ashkenazi Jewish0.000600.00060rare
East Asian0.000220.00022rare
Finnish0.000190.00019rare
European (Non-Finnish)0.000430.00043rare
South Asian0.000520.00052rare
Other0.000330.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Spectrin is the major constituent of the cytoskeletal network underlying the erythrocyte plasma membrane. It associates with band 4.1 and actin to form the cytoskeletal superstructure of the erythrocyte plasma membrane.;
Disease
DISEASE: Elliptocytosis 2 (EL2) [MIM:130600]: A Rhesus-unlinked form of hereditary elliptocytosis, a genetically heterogeneous, autosomal dominant hematologic disorder. It is characterized by variable hemolytic anemia and elliptical or oval red cell shape. {ECO:0000269|PubMed:1541680, ECO:0000269|PubMed:1638030, ECO:0000269|PubMed:1679439, ECO:0000269|PubMed:1878597, ECO:0000269|PubMed:2384601, ECO:0000269|PubMed:2568861, ECO:0000269|PubMed:2568862, ECO:0000269|PubMed:2794061, ECO:0000269|PubMed:7772539, ECO:0000269|PubMed:8018926, ECO:0000269|PubMed:8193371, ECO:0000269|PubMed:8364215}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hereditary pyropoikilocytosis (HPP) [MIM:266140]: Autosomal recessive hematologic disorder characterized by hemolytic anemia, microspherocytosis, poikilocytosis, and an unusual thermal sensitivity of red cells. {ECO:0000269|PubMed:1878597}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spherocytosis 3 (SPH3) [MIM:270970]: Spherocytosis is a hematologic disorder leading to chronic hemolytic anemia and characterized by numerous abnormally shaped erythrocytes which are generally spheroidal. SPH3 is characterized by severe hemolytic anemia. Inheritance is autosomal recessive. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.0869

Intolerance Scores

LoFtool
0.806
RVIS EVS
4.85
RVIS percentile EVS
99.79

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.579

Gene Damage Prediction

AllRecessiveDominant
MendelianHighHighHigh
Primary ImmunodeficiencyHighHighHigh
CancerHighHighHigh
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