rs75981686

Variant names:

• chr6-6145032-C-T
• rs75981686
• NM_000129.4:c.*587G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_000129.4(F13A1):​c.*587G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0084 in 159,076 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0083 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (1 hom.)
• Consequence: F13A1 NM_000129.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.352
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00835 (1271/152262) while in subpopulation NFE AF = 0.0118 (805/68020). AF 95% confidence interval is 0.0112. There are 3 homozygotes in GnomAd4. There are 648 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.*587G>A		3_prime_UTR	Exon 15 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.*587G>A		3_prime_UTR	Exon 15 of 15	ENSP00000264870.3	P00488
	F13A1	ENST00000950947.1		c.*587G>A		3_prime_UTR	Exon 14 of 14	ENSP00000621006.1
	F13A1	ENST00000878383.1		c.*587G>A		3_prime_UTR	Exon 14 of 14	ENSP00000548442.1

Frequencies

GnomAD3 genomes AF: 0.00835 AC: 1270 AN: 152144 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.00969

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.0115

GnomAD4 exome AF: 0.00954 AC: 65 AN: 6814 Hom.: 1 Cov.: 0 AF XY: 0.00922 AC XY: 33 AN XY: 3580

African (AFR) AF: 0.00 AC: 0 AN: 20

American (AMR) AF: 0.00385 AC: 5 AN: 1300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 30

East Asian (EAS) AF: 0.00 AC: 0 AN: 178

South Asian (SAS) AF: 0.00331 AC: 2 AN: 604

European-Finnish (FIN) AF: 0.0305 AC: 16 AN: 524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 10

European-Non Finnish (NFE) AF: 0.00950 AC: 37 AN: 3894

Other (OTH) AF: 0.0197 AC: 5 AN: 254

GnomAD4 genome AF: 0.00835 AC: 1271 AN: 152262 Hom.: 3 Cov.: 32 AF XY: 0.00870 AC XY: 648 AN XY: 74440

African (AFR) AF: 0.00209 AC: 87 AN: 41556

American (AMR) AF: 0.00968 AC: 148 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4818

European-Finnish (FIN) AF: 0.0153 AC: 162 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0118 AC: 805 AN: 68020

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.0112 Hom.: 2

Bravo AF: 0.00756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Factor XIII, A subunit, deficiency of (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.4
DANN	Benign	0.63
PhyloP100		-0.35
Mutation Taster		=100/0	polymorphism

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: rs75981686; hg19: chr6-6145265;