rs5998

chr1-197040668-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001994.3(F13B):c.1806T>C(p.Asn602=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 1,611,534 control chromosomes in the GnomAD database, including 200,693 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (16615 hom., cov: 32)
  • Exomes 𝑓: 0.49 (184078 hom.)
• Consequence: F13B NM_001994.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.430

Genes affected

F13B (HGNC:3534): (coagulation factor XIII B chain) 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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 1-197040668-A-G is Benign according to our data. Variant chr1-197040668-A-G is described in ClinVar as [Benign]. Clinvar id is 258504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197040668-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F13B	NM_001994.3	c.1806T>C	p.Asn602=	synonymous_variant	11/12	ENST00000367412.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F13B	ENST00000367412.2	c.1806T>C	p.Asn602=	synonymous_variant	11/12	1	NM_001994.3	P1
F13B	ENST00000649282.1	c.561T>C	p.Asn187=	synonymous_variant	4/5
F13B	ENST00000490002.1	n.217T>C		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.442 AC: 67131 AN: 151716 Hom.: 16603 Cov.: 32

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.557

Gnomad AMR AF: 0.591

Gnomad ASJ AF: 0.488

Gnomad EAS AF: 0.822

Gnomad SAS AF: 0.604

Gnomad FIN AF: 0.556

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.458

GnomAD3 exomes AF: 0.540 AC: 135126 AN: 250204 Hom.: 39068 AF XY: 0.538 AC XY: 72815 AN XY: 135220

Gnomad AFR exome AF: 0.228

Gnomad AMR exome AF: 0.721

Gnomad ASJ exome AF: 0.488

Gnomad EAS exome AF: 0.818

Gnomad SAS exome AF: 0.589

Gnomad FIN exome AF: 0.566

Gnomad NFE exome AF: 0.472

Gnomad OTH exome AF: 0.524

GnomAD4 exome AF: 0.493 AC: 719945 AN: 1459698 Hom.: 184078 Cov.: 37 AF XY: 0.496 AC XY: 360210 AN XY: 726220

Gnomad4 AFR exome AF: 0.226

Gnomad4 AMR exome AF: 0.707

Gnomad4 ASJ exome AF: 0.492

Gnomad4 EAS exome AF: 0.828

Gnomad4 SAS exome AF: 0.588

Gnomad4 FIN exome AF: 0.562

Gnomad4 NFE exome AF: 0.470

Gnomad4 OTH exome AF: 0.499

GnomAD4 genome AF: 0.442 AC: 67163 AN: 151836 Hom.: 16615 Cov.: 32 AF XY: 0.453 AC XY: 33582 AN XY: 74210

Gnomad4 AFR AF: 0.234

Gnomad4 AMR AF: 0.592

Gnomad4 ASJ AF: 0.488

Gnomad4 EAS AF: 0.822

Gnomad4 SAS AF: 0.603

Gnomad4 FIN AF: 0.556

Gnomad4 NFE AF: 0.473

Gnomad4 OTH AF: 0.462

Alfa AF: 0.476 Hom.: 33934

Bravo AF: 0.439

Asia WGS AF: 0.700 AC: 2424 AN: 3466

EpiCase AF: 0.481

EpiControl AF: 0.482

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Factor XIII, b subunit, deficiency of Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	0.97
Dann	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs5998; hg19: chr1-197009798; COSMIC: COSV66375852;