GeneBe

SERPINC1

protein-coding

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

Gene summary

The protein encoded by this gene, antithrombin III, is a plasma protease inhibitor and a member of the serpin superfamily. This protein inhibits thrombin as well as other activated serine proteases of the coagulation system, and it regulates the blood coagulation cascade. The protein includes two functional domains: the heparin binding-domain at the N-terminus of the mature protein, and the reactive site domain at the C-terminus. The inhibitory activity is enhanced by the presence of heparin. Numerous mutations have been identified for this gene, many of which are known to cause antithrombin-III deficiency which constitutes a strong risk factor for thrombosis. A reduction in the serum level of this protein is associated with severe cases of Coronavirus Disease 19 (COVID-19). [provided by RefSeq, Sep 2020]

Previous symbols:
  • AT3

MANE transcript

NM_000488.4

Inheritance

AR, AD, SD

ClinVar variants

P:149U:162B:90

Top phenotype

Antithrombin III deficiency

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr1:173,903,800-173,917,327

External References & Databases

Ensembl (ENSG00000117601)NCBI Gene (462)OMIM (107300)HGNC:775GenCCUniProt (P01008)AlphaFoldClinVar (SERPINC1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~13.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary antithrombin deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013144

Submitter: Labcorp Genetics (formerly Invitae)

hereditary antithrombin deficiencySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013144

Submitter: Labcorp Genetics (formerly Invitae)

hereditary antithrombin deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013144

Submitter: Ambry Genetics

hereditary antithrombin deficiencyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013144

Submitter: Ambry Genetics

hereditary antithrombin deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013144

Submitter: Genomics England PanelApp

hereditary antithrombin deficiencySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013144

Submitter: Genomics England PanelApp

hereditary antithrombin deficiencySTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0013144

Submitter: PanelApp Australia

hereditary antithrombin deficiencySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013144

Submitter: Orphanet

hereditary antithrombin deficiencyDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0013144

Submitter: ClinGen

SERPINC1 was first reported in relation to antithrombin III deficiency in 1984 (Koide T, et al., 1984, PMID: 6582486). Antithrombin III deficiency is predominantly inherited in an autosomal dominant manner however several biallelic cases have been reported, typically with a more severe presentation, as such the gene-disease relationship has been evaluated for semidominant inheritance. At least 400 unique variants (including missense, nonsense, splicing and frameshift variants) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 18 probands in 6 publications (PMIDs: 6582486, 7734360, 29747524, 28317092, 28892658, 21325262). Variants in this gene segregated with disease in 22 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease relationship is supported by its biochemical function in the regulation of blood coagulation (PMID: 4738234), the functional alteration observed in patient cells (PMID: 7734360), and both null and knock-in mouse models which recapitulate the more severe phenotypes observed in humans (PMID: 11018075 and PMID: 14592998). In summary, SERPINC1 is definitively associated with semidominant antithrombin III deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Clinical Genomic Database (CGD)

Antithrombin III deficiencyAD/AR

Manifestation: Hematologic

Intervention: Hematologic

Rationale: Individuals may be at high risk for thromboembolism, and recognition may allow preventive/prophylactic measures as well as prompt treatment of thromboembolic and related manifestations, including medical treatment with antithrombin, and chronic anticoagulations, which is indicated in asymptomatic individuals as well as those who have previously suffered sequelae

Comments: The inheritance depends on specific variant

Refs: 14347873; 6582486; 3055413; 3350974; 1868237; 2146503; 1671110; 8091378; 16705712; 18208532; 19760264; 21655678; 21655682; 21240680; 21325262; 22997155; 22961244Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SERPINC1 variants in ClinVar

14 Conditions Cataloged
Hereditary antithrombin deficiencyTotal: 383
not providedTotal: 67
SERPINC1-related disorderTotal: 32
Inborn genetic diseasesTotal: 26
not specifiedTotal: 19
Tuberous sclerosis 2Total: 16
Deep venous thrombosisTotal: 4
Thrombophilia with a likely monogenic causeTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000488.4. 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.

EffectPLPVUSLBBSum
synonymous
9
clinvar
77
clinvar
2
clinvar
 88
missense
30
clinvar
40
clinvar
145
clinvar
10
clinvar
1
clinvar
 226
nonsense
12
clinvar
6
clinvar
2
clinvar
 20
start loss
2
clinvar
2
clinvar
 4
frameshift
20
clinvar
15
clinvar
5
clinvar
 40
splice donor/acceptor (+/-2bp)
12
clinvar
10
clinvar
1
clinvar
 23
Total7673162873401

Highest pathogenic variant AF is 0.0026248328

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000488.4RefSeqNP_000479.17MANE Select
ENST00000367698.4EnsemblENSP00000356671.37MANE Select
NM_001365052.2RefSeqNP_001351981.16Standard
NM_001386302.1RefSeqNP_001373231.17Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
serpinc1Danio rerio

Structure: whole organism

Quality: decreased life span

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Complement and coagulation cascades - Homo sapiens (human)
  • Ardeparin Action Pathway
  • Heparin Action Pathway
  • Fondaparinux Action Pathway
  • Enoxaparin Action Pathway

Biological Process

  • acute inflammatory response to antigenic stimulus
  • response to nutrient
  • lactation
  • blood coagulation
  • negative regulation of endopeptidase activity

Molecular Function

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

Cellular Component

  • extracellular region
  • extracellular space
  • endoplasmic reticulum lumen
  • plasma membrane
  • collagen-containing extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000367698
Coding exons
7
Length
13570
Individuals with no LoFs
0
Homozygous LoFs
0
Heterozygous LoFs
0
Defined
0
p
0.00
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.361992610.7630.00001523061
Missense (PolyPhen)7198.9830.717291278
Synonymous0.04801011020.9940.00000596906
Loss of Function4.12019.80.000.00000120235

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Most important serine protease inhibitor in plasma that regulates the blood coagulation cascade. AT-III inhibits thrombin, matriptase-3/TMPRSS7, as well as factors IXa, Xa and XIa. Its inhibitory activity is greatly enhanced in the presence of heparin. {ECO:0000269|PubMed:15853774}.;
Disease
DISEASE: Antithrombin III deficiency (AT3D) [MIM:613118]: An important risk factor for hereditary thrombophilia, a hemostatic disorder characterized by a tendency to recurrent thrombosis. Antithrombin-III deficiency is classified into 4 types. Type I: characterized by a 50% decrease in antigenic and functional levels. Type II: has defects affecting the thrombin-binding domain. Type III: alteration of the heparin-binding domain. Plasma AT-III antigen levels are normal in type II and III. Type IV: consists of miscellaneous group of unclassifiable mutations. {ECO:0000269|PubMed:10997988, ECO:0000269|PubMed:11713457, ECO:0000269|PubMed:11794707, ECO:0000269|PubMed:12353073, ECO:0000269|PubMed:12595305, ECO:0000269|PubMed:12894857, ECO:0000269|PubMed:15164384, ECO:0000269|PubMed:1547341, ECO:0000269|PubMed:1555650, ECO:0000269|PubMed:16908819, ECO:0000269|PubMed:1906811, ECO:0000269|PubMed:2013320, ECO:0000269|PubMed:2229057, ECO:0000269|PubMed:2365065, ECO:0000269|PubMed:23910795, ECO:0000269|PubMed:2781509, ECO:0000269|PubMed:3080419, ECO:0000269|PubMed:3162733, ECO:0000269|PubMed:3179438, ECO:0000269|PubMed:3191114, ECO:0000269|PubMed:3805013, ECO:0000269|PubMed:6582486, ECO:0000269|PubMed:7734359, ECO:0000269|PubMed:7832187, ECO:0000269|PubMed:7878627, ECO:0000269|PubMed:7959685, ECO:0000269|PubMed:7981186, ECO:0000269|PubMed:7989582, ECO:0000269|PubMed:7994035, ECO:0000269|PubMed:8274732, ECO:0000269|PubMed:8443391, ECO:0000269|PubMed:8486379, ECO:0000269|PubMed:9031473, ECO:0000269|PubMed:9157604, ECO:0000269|PubMed:9759613, ECO:0000269|PubMed:9845533, ECO:0000269|Ref.3, ECO:0000269|Ref.55}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.565

Intolerance Scores

RVIS EVS
-0.05
RVIS percentile EVS
50.22

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.143

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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