EPB41

protein-coding

erythrocyte membrane protein band 4.1, the group of FERM domain containing|Erythrocyte membrane protein band 4.1

Gene summary

The protein encoded by this gene, together with spectrin and actin, constitute the red cell membrane cytoskeletal network. This complex plays a critical role in erythrocyte shape and deformability. Mutations in this gene are associated with type 1 elliptocytosis (EL1). Alternatively spliced transcript variants encoding different isoforms have been described for this gene.[provided by RefSeq, Oct 2009]

Previous symbols:

MANE transcript

NM_001376013.1

Inheritance

SD, AD, AR

ClinVar variants

P:43U:167B:48

Top phenotype

Ellipsocytosis 1

gnomAD constraint

pLI —, LoF o/e 0.35

Max pathogenic AF

—

Genomic locus

chr1:28,887,091-29,120,046

External References & Databases

Ensembl (ENSG00000159023)

Transcript & Mutation Effects

hg38 • Region Span ~233.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

elliptocytosis 1STRONG

Inheritance Pattern: SD

Disease ID:MONDO:0012731

Submitter: PanelApp Australia

elliptocytosis 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012731

Submitter: Labcorp Genetics (formerly Invitae)

hereditary elliptocytosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017319

Submitter: Orphanet

elliptocytosis 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012731

Submitter: Labcorp Genetics (formerly Invitae)

elliptocytosis 1DEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0012731

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Ellipsocytosis 1AR

Manifestation: Hematologic

Intervention: Hematologic

Rationale: The recessive form is more severe, and due to anemia, individuals may require transfusions, and/or splenectomy

Refs: 5731934; 7255153; 6894932; 7082842; 3965051; 3995181; 3755799; 3748797; 3674005; 1430200; 16730867; 14692233; 21839655

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EPB41 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 139

Elliptocytosis 1Total: 112

Inborn genetic diseasesTotal: 64

EPB41-related disorderTotal: 24

not specifiedTotal: 20

EPB41-related disordersTotal: 3

Hereditary elliptocytosisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001376013.1. 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			7 clinvar	33 clinvar	1 clinvar	41
missense	2 clinvar	2 clinvar	152 clinvar	13 clinvar	1 clinvar	170
nonsense	6 clinvar	12 clinvar	1 clinvar			19
start loss						0
frameshift	5 clinvar	11 clinvar	1 clinvar			17
splice donor/acceptor (+/-2bp)		5 clinvar	6 clinvar			11
Total	13	30	167	46	2	258

Highest pathogenic variant AF is 0.000019341562

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 217 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001376013.1	RefSeq	NP_001362942.1	19	MANE Select
ENST00000343067.9	Ensembl	ENSP00000345259.4	19	MANE Select
NM_001166005.2	RefSeq	NP_001159477.1	19	Standard
NM_001166006.2	RefSeq	NP_001159478.1	14	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
epb41b	Danio rerio	Structure: nucleate erythrocyte Quality: increased fragility abnormal

Gene / Model

Organism

Observed Phenotype

epb41b

Danio rerio

Structure: nucleate erythrocyte

Quality: increased fragility

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Splicing factor NOVA regulated synaptic proteins
Neuronal System
Neurexins and neuroligins
Protein-protein interactions at synapses
Syndecan-2-mediated signaling events

Biological Process

cell cycle
regulation of cell shape
actin cytoskeleton organization
cortical actin cytoskeleton organization
actomyosin structure organization

Molecular Function

actin binding
structural constituent of cytoskeleton
protein binding
calmodulin binding
1-phosphatidylinositol binding

Cellular Component

nucleus
cytosol
plasma membrane
cytoplasmic side of plasma membrane
postsynaptic density

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000343067
Coding exons: 19
Length: 232951
Individuals with no LoFs: 125695
Homozygous LoFs: 0
Heterozygous LoFs: 53
Defined: 125748
p: 0.000211

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.922	406	462	0.879	0.0000252	5670
Missense (PolyPhen)		210	267.85	0.78402		3173
Synonymous	0.276	160	165	0.973	0.00000926	1625
Loss of Function	4.25	17	49.1	0.346	0.00000263	602

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.00032	0.00032	rare
European (Non-Finnish)	0.00017	0.00017	rare
South Asian	0.00026	0.00026	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Protein 4.1 is a major structural element of the erythrocyte membrane skeleton. It plays a key role in regulating membrane physical properties of mechanical stability and deformability by stabilizing spectrin-actin interaction. Recruits DLG1 to membranes. Required for dynein-dynactin complex and NUMA1 recruitment at the mitotic cell cortex during anaphase (PubMed:23870127). {ECO:0000269|PubMed:23870127}.;
Disease: DISEASE: Elliptocytosis 1 (EL1) [MIM:611804]: A Rhesus-linked 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:3467321}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.359

Intolerance Scores

LoFtool: 0.0367
RVIS EVS: -0.6
RVIS percentile EVS: 18.19

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.945

Gene Damage Prediction

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