EPB42

protein-coding

erythrocyte membrane protein band 4.2, the group of Transglutaminases

Gene summary

Erythrocyte membrane protein band 4.2 is an ATP-binding protein which may regulate the association of protein 3 with ankyrin. It probably has a role in erythrocyte shape and mechanical property regulation. Mutations in the EPB42 gene are associated with recessive spherocytic elliptocytosis and recessively transmitted hereditary hemolytic anemia. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001114134.2

Inheritance

AR, AD

ClinVar variants

P:24U:154B:61

Top phenotype

Spherocytosis, type 5

gnomAD constraint

pLI —, LoF o/e 0.53

Max pathogenic AF

—

Genomic locus

chr15:43,197,227-43,221,018

External References & Databases

Ensembl (ENSG00000166947)

Transcript & Mutation Effects

hg38 • Region Span ~23.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary spherocytosis type 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012985

Submitter: Labcorp Genetics (formerly Invitae)

hereditary spherocytosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019350

Submitter: Orphanet

hereditary spherocytosis type 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012985

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Spherocytosis, type 5AR

Manifestation: Hematologic

Intervention: Hematologic

Rationale: Due to anemia, individuals may require transfusions and/or splenectomy

Refs: 4830746; 4413274; 2963832; 2386772; 2139792; 1558976; 7803799; 7772513; 9734643; 10406914; 12176912; 14636652; 19269200; 21275958

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EPB42 variants in ClinVar

5 Conditions Cataloged

Hereditary spherocytosis type 5Total: 145

not providedTotal: 123

Inborn genetic diseasesTotal: 96

not specifiedTotal: 28

EPB42-related disorderTotal: 13

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001114134.2. 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			4 clinvar	38 clinvar	2 clinvar	44
missense	1 clinvar	5 clinvar	147 clinvar	21 clinvar		174
nonsense	3 clinvar	2 clinvar				5
start loss			1 clinvar			1
frameshift	2 clinvar	10 clinvar	1 clinvar			13
splice donor/acceptor (+/-2bp)	1 clinvar		1 clinvar			2
Total	7	17	154	59	2	239

Highest pathogenic variant AF is 0.00008920728

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001114134.2	RefSeq	NP_001107606.1	13	MANE Select
ENST00000441366.7	Ensembl	ENSP00000396616.2	13	MANE Select
NM_000119.3	RefSeq	NP_000110.2	13	Standard
ENST00000540029.5	Ensembl	ENSP00000444699.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

cell morphogenesis
cytoskeleton organization
regulation of cell shape
peptide cross-linking
hemoglobin metabolic process

Molecular Function

protein-glutamine gamma-glutamyltransferase activity
structural constituent of cytoskeleton
protein binding
ATP binding

Cellular Component

cytoskeleton
plasma membrane
cortical cytoskeleton

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000300215
Coding exons: 13
Length: 115059
Individuals with no LoFs: 125689
Homozygous LoFs: 0
Heterozygous LoFs: 59
Defined: 125748
p: 0.000235

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.939	348	401	0.868	0.0000241	4669
Missense (PolyPhen)		89	122.81	0.7247		1552
Synonymous	0.669	151	162	0.933	0.00000980	1484
Loss of Function	2.63	19	36.1	0.527	0.00000202	391

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00049	0.00049	rare
Finnish	0.00032	0.00032	rare
European (Non-Finnish)	0.00019	0.00018	rare
South Asian	0.00033	0.00033	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probably plays an important role in the regulation of erythrocyte shape and mechanical properties.;
Disease: DISEASE: Spherocytosis 5 (SPH5) [MIM:612690]: Spherocytosis is a hematologic disorder leading to chronic hemolytic anemia and characterized by numerous abnormally shaped erythrocytes which are generally spheroidal. Absence of band 4.2 associated with spur or target erythrocytes has also been reported. {ECO:0000269|PubMed:10406914, ECO:0000269|PubMed:1558976, ECO:0000269|PubMed:7772513, ECO:0000269|PubMed:7819064, ECO:0000269|PubMed:8547071, ECO:0000269|PubMed:8547605}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.127

Intolerance Scores

LoFtool: 0.299
RVIS EVS: -0.19
RVIS percentile EVS: 39.24

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.281

Gene Damage Prediction

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