rs5986

chr6-6174623-T-C

Variant summary

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

The NM_000129.4(F13A1):c.1704A>G(p.Glu568=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0861 in 1,614,104 control chromosomes in the GnomAD database, including 6,513 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (502 hom., cov: 32)
  • Exomes 𝑓: 0.087 (6011 hom.)
• Consequence: F13A1 NM_000129.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.234

Genes affected

F13A1 (HGNC:3531): (coagulation factor XIII A chain) 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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 6-6174623-T-C is Benign according to our data. Variant chr6-6174623-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 255184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-6174623-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.234 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0936 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F13A1	NM_000129.4	c.1704A>G	p.Glu568=	synonymous_variant	12/15	ENST00000264870.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F13A1	ENST00000264870.8	c.1704A>G	p.Glu568=	synonymous_variant	12/15	1	NM_000129.4	P1

Frequencies

GnomAD3 genomes AF: 0.0758 AC: 11527 AN: 152132 Hom.: 502 Cov.: 32

Gnomad AFR AF: 0.0551

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.0672

Gnomad ASJ AF: 0.0806

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0412

Gnomad FIN AF: 0.0913

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0955

Gnomad OTH AF: 0.0850

GnomAD3 exomes AF: 0.0721 AC: 18137 AN: 251432 Hom.: 805 AF XY: 0.0738 AC XY: 10024 AN XY: 135880

Gnomad AFR exome AF: 0.0546

Gnomad AMR exome AF: 0.0477

Gnomad ASJ exome AF: 0.0783

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0505

Gnomad FIN exome AF: 0.0878

Gnomad NFE exome AF: 0.0952

Gnomad OTH exome AF: 0.0877

GnomAD4 exome AF: 0.0872 AC: 127404 AN: 1461854 Hom.: 6011 Cov.: 40 AF XY: 0.0866 AC XY: 62966 AN XY: 727232

Gnomad4 AFR exome AF: 0.0565

Gnomad4 AMR exome AF: 0.0504

Gnomad4 ASJ exome AF: 0.0821

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0507

Gnomad4 FIN exome AF: 0.0860

Gnomad4 NFE exome AF: 0.0959

Gnomad4 OTH exome AF: 0.0800

GnomAD4 genome AF: 0.0757 AC: 11522 AN: 152250 Hom.: 502 Cov.: 32 AF XY: 0.0741 AC XY: 5517 AN XY: 74448

Gnomad4 AFR AF: 0.0550

Gnomad4 AMR AF: 0.0670

Gnomad4 ASJ AF: 0.0806

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0408

Gnomad4 FIN AF: 0.0913

Gnomad4 NFE AF: 0.0956

Gnomad4 OTH AF: 0.0836

Alfa AF: 0.0929 Hom.: 965

Bravo AF: 0.0738

Asia WGS AF: 0.0270 AC: 95 AN: 3478

EpiCase AF: 0.102

EpiControl AF: 0.101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Factor XIII, A subunit, deficiency of Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	3.0
Dann	Benign	0.44

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: rs5986; hg19: chr6-6174856; COSMIC: COSV53557044;