chr6-6174623-T-C

Variant names:

• chr6-6174623-T-C
• rs5986
• NM_000129.4:c.1704A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000129.4(F13A1):​c.1704A>G​(p.Glu568Glu) 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:4
• Conservation: PhyloP100: 0.234
• Publications: 8 publications found

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]

F13A1 Gene-Disease associations (from GenCC):

• factor XIII, A subunit, deficiency of

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen
• congenital factor XIII deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 255184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000129.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F13A1	NM_000129.4	MANE Select	c.1704A>G	p.Glu568Glu	synonymous	Exon 12 of 15	NP_000120.2	P00488

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F13A1	ENST00000264870.8	TSL:1 MANE Select	c.1704A>G	p.Glu568Glu	synonymous	Exon 12 of 15	ENSP00000264870.3	P00488
	F13A1	ENST00000950947.1		c.1704A>G	p.Glu568Glu	synonymous	Exon 11 of 14	ENSP00000621006.1
	F13A1	ENST00000878383.1		c.1515A>G	p.Glu505Glu	synonymous	Exon 11 of 14	ENSP00000548442.1

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

GnomAD2 exomes AF: 0.0721 AC: 18137 AN: 251432 AF XY: 0.0738

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 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

African (AFR) AF: 0.0565 AC: 1893 AN: 33480

American (AMR) AF: 0.0504 AC: 2256 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0821 AC: 2147 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0507 AC: 4375 AN: 86254

European-Finnish (FIN) AF: 0.0860 AC: 4593 AN: 53420

Middle Eastern (MID) AF: 0.121 AC: 698 AN: 5768

European-Non Finnish (NFE) AF: 0.0959 AC: 106611 AN: 1111978

Other (OTH) AF: 0.0800 AC: 4830 AN: 60394

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

African (AFR) AF: 0.0550 AC: 2284 AN: 41552

American (AMR) AF: 0.0670 AC: 1025 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0806 AC: 280 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5164

South Asian (SAS) AF: 0.0408 AC: 197 AN: 4826

European-Finnish (FIN) AF: 0.0913 AC: 969 AN: 10616

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0956 AC: 6499 AN: 68010

Other (OTH) AF: 0.0836 AC: 177 AN: 2116

Alfa AF: 0.0910 Hom.: 1152

Bravo AF: 0.0738

Asia WGS AF: 0.0270 AC: 95 AN: 3478

EpiCase AF: 0.102

EpiControl AF: 0.101

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Factor XIII, A subunit, deficiency of (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	3.0
DANN	Benign	0.44
PhyloP100		0.23
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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