F13A1

protein-coding

coagulation factor XIII A chain, the group of MicroRNA protein coding host genes|Transglutaminases

Gene summary

This gene encodes the coagulation factor XIII A subunit. Coagulation factor XIII is the last zymogen to become activated in the blood coagulation cascade. Plasma factor XIII is a heterotetramer composed of 2 A subunits and 2 B subunits. The A subunits have catalytic function, and the B subunits do not have enzymatic activity and may serve as plasma carrier molecules. Platelet factor XIII is comprised only of 2 A subunits, which are identical to those of plasma origin. Upon cleavage of the activation peptide by thrombin and in the presence of calcium ion, the plasma factor XIII dissociates its B subunits and yields the same active enzyme, factor XIIIa, as platelet factor XIII. This enzyme acts as a transglutaminase to catalyze the formation of gamma-glutamyl-epsilon-lysine crosslinking between fibrin molecules, thus stabilizing the fibrin clot. It also crosslinks alpha-2-plasmin inhibitor, or fibronectin, to the alpha chains of fibrin. Factor XIII deficiency is classified into two categories: type I deficiency, characterized by the lack of both the A and B subunits; and type II deficiency, characterized by the lack of the A subunit alone. These defects can result in a lifelong bleeding tendency, defective wound healing, and habitual abortion. [provided by RefSeq, Jul 2008]

Previous symbols:

F13A

MANE transcript

NM_000129.4

Inheritance

ClinVar variants

P:52U:136B:48

Top phenotype

Factor XIIIA, A subunit, deficiency of

gnomAD constraint

pLI —, LoF o/e 0.5

Max pathogenic AF

—

Genomic locus

chr6:6,144,084-6,321,013

External References & Databases

Ensembl (ENSG00000124491)

Transcript & Mutation Effects

hg38 • Region Span ~176.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

factor XIII, A subunit, deficiency ofDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013187

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

congenital factor XIII deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018029

Submitter: Orphanet

factor XIII, A subunit, deficiency ofDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013187

Submitter: ClinGen

The relationship between F13A1 and Factor XIIIA deficiency inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of February, 2019. This association was made using case-level and experimental data. At least 25 pathogenic variants in this gene are reported in ClinVar, including nonsense, frameshift, missense and splicing variants. F13A1 encodes A subunits, which have catalytic function, of the coagulation factor XIII. FXIII is a transglutaminase that forms intramolecular gamma-glutamyl-epsilon-lysine crosslinking between fibrin molecules to stabilize blood clots. Factor XIIIA deficiency is characterized by a bleeding diathesis, poor wound healing and reduced Factor XIII activity levels. Mutations in F13A1 were first associated with this disease in humans as early as 1992 by Board et al. (PMID: 8324218) and Kamura et al (PMID: 1644910). Summary of Case Level Data (12 points): The association is seen in at least 10 probands in 7 publications (PMID: 9531593, 1353995, 12100162, 1644910, 7727776, 8025280, 19438481). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease is expected to be biallelic loss of function. Summary of Experimental Data (4.5 points): Mouse models recapitulating FXIII deficiency and rescue using rFXIII have been reported (PMID: 12529747, 18224415). In summary, the F13A1 - Factor XIIIA deficiency gene-disease relationship is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hemostasis/Thrombosis GCEP on July 22, 2020. (SOP Version 6).

factor XIII, A subunit, deficiency ofSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013187

Submitter: Labcorp Genetics (formerly Invitae)

factor XIII, A subunit, deficiency ofSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013187

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Factor XIIIA, A subunit, deficiency ofAR

Manifestation: Hematologic

Intervention: Hematologic; Pharmacogenomic

Rationale: Individuals have increased bleeding and poor wound healing; awareness and management of bleeding risk in certain situations (eg, obstetric event or surgery) may decrease morbidity; Precautions should be taken related to certain agents that may provoke/worsen bleeding risk

Refs: 1644910; 8025280; 7727776; 8547636; 9459313; 10365735; 12072871; 12456499; 17393027; 19438481; 20108427; 21512576

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to F13A1 variants in ClinVar

13 Conditions Cataloged

Inborn genetic diseasesTotal: 85

Factor XIII, A subunit, deficiency ofTotal: 84

not providedTotal: 62

F13A1-related disorderTotal: 47

not specifiedTotal: 36

Thrombophilia due to thrombin defectTotal: 9

Myocardial infarction, susceptibility toTotal: 4

F13A1-related disordersTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000129.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	33 clinvar		38
missense	10 clinvar	12 clinvar	130 clinvar	15 clinvar		167
nonsense	5 clinvar	5 clinvar				10
start loss						0
frameshift	8 clinvar	6 clinvar				14
splice donor/acceptor (+/-2bp)	2 clinvar	4 clinvar	1 clinvar			7
Total	25	27	136	48	0	236

Highest pathogenic variant AF is 0.00008426897

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000129.4	RefSeq	NP_000120.2	14	MANE Select
ENST00000264870.8	Ensembl	ENSP00000264870.3	14	MANE Select
ENST00000414279.5	Ensembl	ENSP00000413334.1	3	Standard
ENST00000431222.6	Ensembl	ENSP00000416295.2	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Complement and coagulation cascades - Homo sapiens (human)
Aminocaproic Acid Action Pathway
Tranexamic Acid Action Pathway
Urokinase Action Pathway
Reteplase Action Pathway

Biological Process

platelet degranulation
blood coagulation
peptide cross-linking
cytokine-mediated signaling pathway
blood coagulation, fibrin clot formation

Molecular Function

protein-glutamine gamma-glutamyltransferase activity
metal ion binding

Cellular Component

extracellular region
platelet alpha granule lumen
collagen-containing extracellular matrix
blood microparticle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264870
Coding exons: 14
Length: 176929
Individuals with no LoFs: 125640
Homozygous LoFs: 0
Heterozygous LoFs: 108
Defined: 125748
p: 0.000430

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.05	356	416	0.855	0.0000248	4826
Missense (PolyPhen)		125	173.55	0.72027		2068
Synonymous	-0.773	175	162	1.08	0.0000104	1409
Loss of Function	2.79	18	36.1	0.498	0.00000190	417

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.0020	0.0020	notable
European (Non-Finnish)	0.00039	0.00035	rare
South Asian	0.00026	0.00026	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Factor XIII is activated by thrombin and calcium ion to a transglutaminase that catalyzes the formation of gamma-glutamyl- epsilon-lysine cross-links between fibrin chains, thus stabilizing the fibrin clot. Also cross-link alpha-2-plasmin inhibitor, or fibronectin, to the alpha chains of fibrin. {ECO:0000269|PubMed:27363989}.;
Disease: DISEASE: Factor XIII subunit A deficiency (FA13AD) [MIM:613225]: An autosomal recessive hematologic disorder characterized by a life-long bleeding tendency, impaired wound healing and spontaneous abortion in affected women. {ECO:0000269|PubMed:1353995, ECO:0000269|PubMed:20179087, ECO:0000269|PubMed:24286209, ECO:0000269|PubMed:24329762, ECO:0000269|PubMed:24889649, ECO:0000269|PubMed:27363989}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.592

Intolerance Scores

LoFtool: 0.183
RVIS EVS: 0.25
RVIS percentile EVS: 69.66

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.739

Gene Damage Prediction

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