HEPH

protein-coding

hephaestin

Gene summary

This gene encodes a member of the multicopper oxidase protein family. The encoded protein is involved in the transport of dietary iron from epithelial cells of the intestinal lumen into the circulatory system, and may be involved in copper transport and homeostasis. In mouse, defects in this gene can lead to severe microcytic anemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

MANE transcript

NM_001367233.3

Inheritance

ClinVar variants

U:246B:10

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chrX:66,162,671-66,268,867

External References & Databases

Ensembl (ENSG00000089472)

Transcript & Mutation Effects

hg38 • Region Span ~106.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary hemochromatosisMODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0006507

Submitter: Genomics England PanelApp

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HEPH variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 133

not providedTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001367233.3. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			22 clinvar	1 clinvar		23
missense			193 clinvar	8 clinvar	1 clinvar	202
nonsense			10 clinvar			10
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			21 clinvar			21
Total	0	0	246	9	1	256

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 164 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001367233.3	RefSeq	NP_001354162.2	20	MANE Select
ENST00000343002.7	Ensembl	ENSP00000343939.2	20	MANE Select
NM_001130860.6	RefSeq	NP_001124332.2	20	Standard
NM_001282141.3	RefSeq	NP_001269070.2	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Porphyrin and chlorophyll metabolism - Homo sapiens (human)
Mineral absorption - Homo sapiens (human)
Transport of bile salts and organic acids, metal ions and amine compounds
SLC-mediated transmembrane transport
Transport of small molecules

Biological Process

copper ion transport
iron ion transport
cellular iron ion homeostasis
iron ion homeostasis
oxidation-reduction process

Molecular Function

ferroxidase activity
copper ion binding
ferrous iron binding
oxidoreductase activity

Cellular Component

plasma membrane
integral component of membrane
basolateral plasma membrane
perinuclear region of cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000519389
Coding exons: 21
Length: 106319
Individuals with no LoFs: 125713
Homozygous LoFs: 10
Heterozygous LoFs: 21
Defined: 125744
p: 0.000123

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.715	485	443	1.10	0.0000327	8011
Missense (PolyPhen)		149	171.04	0.87115		3154
Synonymous	-1.96	188	157	1.20	0.0000109	2314
Loss of Function	3.76	15	41.0	0.366	0.00000327	654

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00023	0.00018	rare
Latino/Admixed American	0.000076	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00030	0.00022	rare
Finnish	0.00038	0.00028	rare
European (Non-Finnish)	0.00016	0.00011	rare
South Asian	0.00011	0.000065	rare
Other	0.00023	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May function as a ferroxidase for ferrous (II) to ferric ion (III) conversion and may be involved in copper transport and homeostasis. Implicated in iron homeostasis and may mediate iron efflux associated to ferroportin 1.;

Recessive Scores

pRec: 0.375

Intolerance Scores

LoFtool: 0.0196
RVIS EVS: 0.38
RVIS percentile EVS: 75.65

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.388

Gene Damage Prediction

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