AFP

protein-coding

alpha fetoprotein

Gene summary

This gene encodes alpha-fetoprotein, a major plasma protein produced by the yolk sac and the liver during fetal life. Alpha-fetoprotein expression in adults is often associated with hepatocarcinoma and with teratoma, and has prognostic value for managing advanced gastric cancer. However, hereditary persistance of alpha-fetoprotein may also be found in individuals with no obvious pathology. The protein is thought to be the fetal counterpart of serum albumin, and the alpha-fetoprotein and albumin genes are present in tandem in the same transcriptional orientation on chromosome 4. Alpha-fetoprotein is found in monomeric as well as dimeric and trimeric forms, and binds copper, nickel, fatty acids and bilirubin. The level of alpha-fetoprotein in amniotic fluid is used to measure renal loss of protein to screen for spina bifida and anencephaly. [provided by RefSeq, Oct 2019]

Previous symbols:

HPAFP

MANE transcript

NM_001134.3

Inheritance

AD, AR

ClinVar variants

P:3U:79B:17

Top phenotype

AFP deficiency, congenital; Hereditary persistence of AFP

gnomAD constraint

pLI —, LoF o/e 0.64

Max pathogenic AF

—

Genomic locus

chr4:73,431,138-73,456,174

External References & Databases

Ensembl (ENSG00000081051)

Transcript & Mutation Effects

hg38 • Region Span ~25.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary persistence of alpha-fetoproteinSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014425

Submitter: Orphanet

congenital deficiency in alpha-fetoproteinMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014424

Submitter: PanelApp Australia

hereditary persistence of alpha-fetoproteinMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014425

Submitter: PanelApp Australia

congenital deficiency in alpha-fetoproteinNO_KNOWN

Inheritance Pattern: AR

Disease ID:MONDO:0014424

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

AFP deficiency, congenital; Hereditary persistence of AFPAD/AR

Manifestation: General

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

Refs: 1690155; 1379776; 7684942; 15280901; 18854864

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AFP variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 84

not providedTotal: 7

Alpha-fetoprotein, hereditary persistence ofTotal: 5

AFP-related disorderTotal: 4

Alpha-fetoprotein deficiencyTotal: 2

Premature ovarian failureTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001134.3. 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				9 clinvar	2 clinvar	11
missense		1 clinvar	79 clinvar	3 clinvar	2 clinvar	85
nonsense	1 clinvar					1
start loss						0
frameshift	1 clinvar					1
splice donor/acceptor (+/-2bp)				1 clinvar		1
Total	2	1	79	13	4	99

Highest pathogenic variant AF is 0.000015491501

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001134.3	RefSeq	NP_001125.1	14	MANE Select
ENST00000395792.7	Ensembl	ENSP00000379138.2	14	MANE Select
NM_001354717.2	RefSeq	NP_001341646.2	11	Standard
ENST00000226359.2	Ensembl	ENSP00000226359.2	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Hippo signaling pathway - Homo sapiens (human)
Post-translational protein phosphorylation
Post-translational protein modification
Metabolism of proteins
p73 transcription factor network

Biological Process

ovulation from ovarian follicle
progesterone metabolic process
post-translational protein modification
cellular protein metabolic process
SMAD protein signal transduction

Molecular Function

protein binding
metal ion binding

Cellular Component

extracellular space
endoplasmic reticulum lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000395792
Coding exons: 14
Length: 25037
Individuals with no LoFs: 125675
Homozygous LoFs: 0
Heterozygous LoFs: 73
Defined: 125748
p: 0.000290

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.185	302	311	0.970	0.0000148	4007
Missense (PolyPhen)		70	97.289	0.71951		1326
Synonymous	0.371	106	111	0.955	0.00000542	1096
Loss of Function	1.99	23	35.8	0.642	0.00000178	448

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0015	0.0015	notable
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00024	0.00024	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binds copper, nickel, and fatty acids as well as, and bilirubin less well than, serum albumin. Only a small percentage (less than 2%) of the human AFP shows estrogen-binding properties.;
Disease: DISEASE: Alpha-fetoprotein deficiency (AFPD) [MIM:615969]: A benign condition characterized by undetectable AFP levels in the amniotic fluid. Affected individuals are asymptomatic and present normal development. {ECO:0000269|PubMed:15280901, ECO:0000269|PubMed:18854864}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Alpha-fetoprotein, hereditary persistence (HPAFP) [MIM:615970]: A benign autosomal dominant condition characterized by continued expression of alpha-fetoprotein in adult life. {ECO:0000269|PubMed:7684942}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.750

Intolerance Scores

LoFtool: 0.859
RVIS EVS: 0.29
RVIS percentile EVS: 71.57

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.928

Gene Damage Prediction

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