6-6320575-T-G

Position:

• chr6-6320575-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000129.4(F13A1):​c.-19+12A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 466,414 control chromosomes in the GnomAD database, including 177,234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (59146 hom., cov: 33)
  • Exomes 𝑓: 0.87 (118088 hom.)
• Consequence: F13A1 NM_000129.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.36

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]

LOC124901253 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-6320575-T-G is Benign according to our data. Variant chr6-6320575-T-G is described in ClinVar as [Benign]. Clinvar id is 357680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-6320575-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.933 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F13A1	NM_000129.4	c.-19+12A>C		intron_variant		ENST00000264870.8	NP_000120.2
LOC124901253	XR_007059428.1	n.55-9178T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F13A1	ENST00000264870.8	c.-19+12A>C		intron_variant		1	NM_000129.4	ENSP00000264870.3
F13A1	ENST00000431222.6	c.144+12A>C		intron_variant		4		ENSP00000416295.2
F13A1	ENST00000451619.1	c.54+12A>C		intron_variant		2		ENSP00000411114.1
F13A1	ENST00000414279.5	c.-19+12A>C		intron_variant		4		ENSP00000413334.1

Frequencies

GnomAD3 genomes AF: 0.881 AC: 134043 AN: 152090 Hom.: 59096 Cov.: 33

Gnomad AFR AF: 0.890

Gnomad AMI AF: 0.863

Gnomad AMR AF: 0.866

Gnomad ASJ AF: 0.855

Gnomad EAS AF: 0.956

Gnomad SAS AF: 0.795

Gnomad FIN AF: 0.854

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.887

Gnomad OTH AF: 0.872

GnomAD3 exomes AF: 0.870 AC: 125895 AN: 144754 Hom.: 54922 AF XY: 0.866 AC XY: 67303 AN XY: 77740

Gnomad AFR exome AF: 0.892

Gnomad AMR exome AF: 0.857

Gnomad ASJ exome AF: 0.858

Gnomad EAS exome AF: 0.954

Gnomad SAS exome AF: 0.788

Gnomad FIN exome AF: 0.860

Gnomad NFE exome AF: 0.894

Gnomad OTH exome AF: 0.860

GnomAD4 exome AF: 0.866 AC: 271953 AN: 314206 Hom.: 118088 Cov.: 0 AF XY: 0.859 AC XY: 152366 AN XY: 177384

Gnomad4 AFR exome AF: 0.889

Gnomad4 AMR exome AF: 0.857

Gnomad4 ASJ exome AF: 0.854

Gnomad4 EAS exome AF: 0.956

Gnomad4 SAS exome AF: 0.792

Gnomad4 FIN exome AF: 0.862

Gnomad4 NFE exome AF: 0.890

Gnomad4 OTH exome AF: 0.870

GnomAD4 genome AF: 0.881 AC: 134148 AN: 152208 Hom.: 59146 Cov.: 33 AF XY: 0.879 AC XY: 65428 AN XY: 74418

Gnomad4 AFR AF: 0.890

Gnomad4 AMR AF: 0.866

Gnomad4 ASJ AF: 0.855

Gnomad4 EAS AF: 0.956

Gnomad4 SAS AF: 0.795

Gnomad4 FIN AF: 0.854

Gnomad4 NFE AF: 0.887

Gnomad4 OTH AF: 0.869

Alfa AF: 0.882 Hom.: 71507

Bravo AF: 0.887

Asia WGS AF: 0.838 AC: 2915 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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

Factor XIII, A subunit, deficiency of Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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

Jun 18, 2021

This variant is associated with the following publications: (PMID: 21512576, 23508224) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.34

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: rs2815822; hg19: chr6-6320808;