F13B

protein-coding

coagulation factor XIII B chain, the group of Sushi domain containing

Gene summary

This gene encodes coagulation factor XIII B 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 a plasma carrier molecules. Platelet factor XIII is comprised only of 2 A subunits, which are identical to those of plasma origin. Upon activation by the 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. 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]

MANE transcript

NM_001994.3

Inheritance

ClinVar variants

P:16U:114B:19

Top phenotype

Factor XIIIB deficiency

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr1:197,038,741-197,067,260

External References & Databases

Ensembl (ENSG00000143278)

Transcript & Mutation Effects

hg38 • Region Span ~28.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

factor XIII, b subunit, deficiency ofDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013190

Submitter: ClinGen

The relationship between F13B and Factor XIIIB deficiency inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of July, 2020. This association was made using case-level and experimental data. Only a few pathogenic variants in this gene are reported in ClinVar, including frameshift, missense and splicing variants. F13B encodes the B subunits, which act as carrier proteins, 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 XIIIB deficiency is characterized by a bleeding diathesis, poor wound healing and reduced Factor XIII activity and antigen levels. Mutations in F13B were first associated with this disease in humans as early as 1993 by Hashiguchi et al. (PMID: 8324218). Summary of Case Level Data (10 points): The association is seen in at least 6 probands in 5 publications (PMID: 11313256, 20331752, 8324218, 8639893, 31064749). The mechanism for disease is expected to be biallelic loss of function. A number of heterozygous individuals with Factor XIIIB deficiency have also been reported, but have not been scored in this curation (PMID: 20331752, 23913518, 26247044). Summary of Experimental Data (2.5 points): A mouse model recapitulating FXIII deficiency and rescue using rFXIIIB have been reported (PMID: 18224415). In summary, the F13B - Factor XIIIB 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, b subunit, deficiency ofSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013190

Submitter: Labcorp Genetics (formerly Invitae)

factor XIII, b subunit, deficiency ofSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013190

Submitter: PanelApp Australia

congenital factor XIII deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018029

Submitter: Orphanet

factor XIII, b subunit, deficiency ofMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013190

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Factor XIIIB deficiencyAR

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: 2334637; 8324218; 11313256; 20331752; 21640452

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to F13B variants in ClinVar

10 Conditions Cataloged

Inborn genetic diseasesTotal: 69

Factor XIII, b subunit, deficiency ofTotal: 58

not providedTotal: 28

not specifiedTotal: 21

F13B-related disorderTotal: 16

Factor XIII deficiencyTotal: 1

ThrombusTotal: 1

Coagulation factor deficiency syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001994.3. 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			6 clinvar	12 clinvar		18
missense	1 clinvar	1 clinvar	105 clinvar	7 clinvar		114
nonsense	3 clinvar	3 clinvar				6
start loss						0
frameshift	4 clinvar	2 clinvar	2 clinvar			8
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	1 clinvar			3
Total	9	7	114	19	0	149

Highest pathogenic variant AF is 0.000026041505

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001994.3	RefSeq	NP_001985.2	12	MANE Select
ENST00000367412.2	Ensembl	ENSP00000356382.2	12	MANE Select
ENST00000649282.1	Ensembl	ENSP00000497116.1	5	Standard
ENST00000895399.1	Ensembl	ENSP00000565458.1	11	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

blood coagulation
blood coagulation, fibrin clot formation
negative regulation of cellular protein catabolic process

Cellular Component

extracellular region

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367412
Coding exons: 12
Length: 28077
Individuals with no LoFs: 125641
Homozygous LoFs: 1
Heterozygous LoFs: 78
Defined: 125720
p: 0.000314

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.568	312	342	0.913	0.0000162	4303
Missense (PolyPhen)		122	129.68	0.94076		1549
Synonymous	0.379	114	119	0.956	0.00000605	1183
Loss of Function	2.24	20	34.1	0.587	0.00000143	502

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00044	0.00043	rare
Ashkenazi Jewish	0.00011	0.000099	rare
East Asian	0.00027	0.00027	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00024	0.00023	rare
South Asian	0.00098	0.00095	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The B chain of factor XIII is not catalytically active, but is thought to stabilize the A subunits and regulate the rate of transglutaminase formation by thrombin. {ECO:0000303|PubMed:21742792, ECO:0000303|PubMed:3021194}.;
Disease: DISEASE: Factor XIII subunit B deficiency (FA13BD) [MIM:613235]: An autosomal recessive hematologic disorder characterized by a life-long bleeding tendency, impaired wound healing and spontaneous abortion in affected women. {ECO:0000269|PubMed:11313256, ECO:0000269|PubMed:20331752, ECO:0000269|PubMed:26247044, ECO:0000269|PubMed:8324218}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.258

Intolerance Scores

LoFtool: 0.508
RVIS EVS: 0.73
RVIS percentile EVS: 86.21

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.674

Gene Damage Prediction

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