rs6003

Positions:

• chr1-197061891-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001994.3(F13B):​c.344G>A​(p.Arg115His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.883 in 1,612,650 control chromosomes in the GnomAD database, including 638,098 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (48909 hom., cov: 30)
  • Exomes 𝑓: 0.89 (589189 hom.)
• Consequence: F13B NM_001994.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.438

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 -18 ACMG points.

• PM1: In a disulfide_bond (size 44) in uniprot entity F13B_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001994.3
• BP4: Computational evidence support a benign effect (MetaRNN=6.8317645E-6).
• BP6: Variant 1-197061891-C-T is Benign according to our data. Variant chr1-197061891-C-T is described in ClinVar as [Benign]. Clinvar id is 16520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197061891-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F13B	NM_001994.3	c.344G>A	p.Arg115His	missense_variant	3/12	ENST00000367412.2	NP_001985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F13B	ENST00000367412.2	c.344G>A	p.Arg115His	missense_variant	3/12	1	NM_001994.3	ENSP00000356382.2

Frequencies

GnomAD3 genomes AF: 0.770 AC: 116834 AN: 151792 Hom.: 48890 Cov.: 30

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.955

Gnomad AMR AF: 0.868

Gnomad ASJ AF: 0.902

Gnomad EAS AF: 0.979

Gnomad SAS AF: 0.896

Gnomad FIN AF: 0.929

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.910

Gnomad OTH AF: 0.800

GnomAD3 exomes AF: 0.882 AC: 220834 AN: 250328 Hom.: 99690 AF XY: 0.890 AC XY: 120395 AN XY: 135260

Gnomad AFR exome AF: 0.391

Gnomad AMR exome AF: 0.932

Gnomad ASJ exome AF: 0.894

Gnomad EAS exome AF: 0.982

Gnomad SAS exome AF: 0.898

Gnomad FIN exome AF: 0.930

Gnomad NFE exome AF: 0.906

Gnomad OTH exome AF: 0.897

GnomAD4 exome AF: 0.894 AC: 1306317 AN: 1460740 Hom.: 589189 Cov.: 43 AF XY: 0.896 AC XY: 651004 AN XY: 726666

Gnomad4 AFR exome AF: 0.382

Gnomad4 AMR exome AF: 0.927

Gnomad4 ASJ exome AF: 0.900

Gnomad4 EAS exome AF: 0.982

Gnomad4 SAS exome AF: 0.898

Gnomad4 FIN exome AF: 0.932

Gnomad4 NFE exome AF: 0.904

Gnomad4 OTH exome AF: 0.879

GnomAD4 genome AF: 0.770 AC: 116902 AN: 151910 Hom.: 48909 Cov.: 30 AF XY: 0.775 AC XY: 57553 AN XY: 74276

Gnomad4 AFR AF: 0.403

Gnomad4 AMR AF: 0.868

Gnomad4 ASJ AF: 0.902

Gnomad4 EAS AF: 0.979

Gnomad4 SAS AF: 0.897

Gnomad4 FIN AF: 0.929

Gnomad4 NFE AF: 0.910

Gnomad4 OTH AF: 0.802

Alfa AF: 0.889 Hom.: 156847

Bravo AF: 0.749

ESP6500AA AF: 0.409 AC: 1804

ESP6500EA AF: 0.907 AC: 7801

ExAC AF: 0.872 AC: 105765

Asia WGS AF: 0.911 AC: 3166 AN: 3476

EpiCase AF: 0.905

EpiControl AF: 0.909

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 27821352, 12941053, 25384012, 16241947, 12456499) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Factor XIII, b subunit, deficiency of Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	- -

Venous thrombosis, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Nov 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.64
DANN	Benign	0.31
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0000068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.79	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.037
Sift	Benign	0.38	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.018
MPC		0.16
ClinPred		0.0072	T
GERP RS		-0.82
Varity_R		0.032
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6003; hg19: chr1-197031021;