SERPINA1

protein-coding

serpin family A member 1, the group of Serpin peptidase inhibitors

Gene summary

The protein encoded by this gene is a serine protease inhibitor belonging to the serpin superfamily whose targets include elastase, plasmin, thrombin, trypsin, chymotrypsin, and plasminogen activator. This protein is produced in the liver, the bone marrow, by lymphocytic and monocytic cells in lymphoid tissue, and by the Paneth cells of the gut. Defects in this gene are associated with chronic obstructive pulmonary disease, emphysema, and chronic liver disease. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2020]

Previous symbols:

MANE transcript

NM_000295.5

Inheritance

AR, AD

ClinVar variants

P:88U:106B:225

Top phenotype

Alpha-1-Antitrypsin deficiency

gnomAD constraint

pLI —, LoF o/e 1

Max pathogenic AF

—

Genomic locus

chr14:94,376,747-94,390,693

External References & Databases

Ensembl (ENSG00000197249)

Transcript & Mutation Effects

hg38 • Region Span ~13.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cystic fibrosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009061

Submitter: Orphanet

alpha 1-antitrypsin deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013282

Submitter: Orphanet

alpha 1-antitrypsin deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013282

Submitter: Genomics England PanelApp

alpha 1-antitrypsin deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013282

Submitter: Genomics England PanelApp

hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutationSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015801

Submitter: Orphanet

alpha 1-antitrypsin deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013282

Submitter: Labcorp Genetics (formerly Invitae)

alpha 1-antitrypsin deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013282

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Alpha-1-Antitrypsin deficiencyAR

Manifestation: Gastrointestinal; Pulmonary

Intervention: Gastrointestinal; Pulmonary

Rationale: Medical treatment (augmentation therapy with purified alpha-1-antitrypsin, Vitamin E supplementation) can be helpful for pulmonary and hepatic manifestations; Exacerbating factors (eg, smoking) should be avoided; Liver transplantation may be necessary in individuals with severe liver manifestations

Refs: 4240153; 4117022; 3494198; 2185272; 2035327; 7875269; 8066566; 10898319; 12740257; 11320399; 12452881; 12574076; 14522813; 15282394; 15214923; 20301692; 21457231; 21752289; 22016686; 22215832; 22330941; 22500781; 22536580; 22933512; 23055718; 23251618; 23766346

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SERPINA1 variants in ClinVar

51 Conditions Cataloged

Alpha-1-antitrypsin deficiencyTotal: 351

not providedTotal: 107

SERPINA1-related disorderTotal: 102

Inborn genetic diseasesTotal: 52

not specifiedTotal: 27

See casesTotal: 2

Pneumothorax - familialTotal: 2

Hereditary angioedema with normal C1InhTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000295.5. 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			3 clinvar	161 clinvar	2 clinvar	166
missense	8 clinvar	21 clinvar	101 clinvar	53 clinvar	7 clinvar	190
nonsense	7 clinvar	7 clinvar				14
start loss	1 clinvar	1 clinvar				2
frameshift	19 clinvar	16 clinvar			2 clinvar	37
splice donor/acceptor (+/-2bp)	3 clinvar	5 clinvar	2 clinvar			10
Total	38	50	106	214	11	419

Highest pathogenic variant AF is 0.015862918

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 115 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000295.5	RefSeq	NP_000286.3	4	MANE Select
ENST00000393087.9	Ensembl	ENSP00000376802.4	4	MANE Select
NM_001002235.3	RefSeq	NP_001002235.1	4	Standard
NM_001002236.3	RefSeq	NP_001002236.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Complement and coagulation cascades - Homo sapiens (human)
Nuclear Receptors Meta-Pathway
NRF2 pathway
Lung fibrosis
Dengue-2 Interactions with Complement and Coagulation Cascades

Biological Process

platelet degranulation
endoplasmic reticulum to Golgi vesicle-mediated transport
acute-phase response
blood coagulation
negative regulation of endopeptidase activity

Molecular Function

protease binding
serine-type endopeptidase inhibitor activity
protein binding
identical protein binding

Cellular Component

Golgi membrane
extracellular region
extracellular space
endoplasmic reticulum
endoplasmic reticulum lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000448921
Coding exons: 4
Length: 13947
Individuals with no LoFs: 125725
Homozygous LoFs: 0
Heterozygous LoFs: 23
Defined: 125748
p: 0.0000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.373	242	226	1.07	0.0000121	2771
Missense (PolyPhen)		54	58.882	0.91708		778
Synonymous	-0.0692	103	102	1.01	0.00000647	825
Loss of Function	0.00374	11	11.0	0.999	4.78e-7	140

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000097	0.000097	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Inhibitor of serine proteases. Its primary target is elastase, but it also has a moderate affinity for plasmin and thrombin. Irreversibly inhibits trypsin, chymotrypsin and plasminogen activator. The aberrant form inhibits insulin-induced NO synthesis in platelets, decreases coagulation time and has proteolytic activity against insulin and plasmin.;
Disease: DISEASE: Alpha-1-antitrypsin deficiency (A1ATD) [MIM:613490]: A disorder whose most common manifestation is emphysema, which becomes evident by the third to fourth decade. A less common manifestation of the deficiency is liver disease, which occurs in children and adults, and may result in cirrhosis and liver failure. Environmental factors, particularly cigarette smoking, greatly increase the risk of emphysema at an earlier age. {ECO:0000269|PubMed:1905728, ECO:0000269|PubMed:2227940, ECO:0000269|PubMed:2390072}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.798

Intolerance Scores

LoFtool: 0.00462
RVIS EVS: 0.53
RVIS percentile EVS: 81.01

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.975

Gene Damage Prediction

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