6-6145459-C-T

Position:

• chr6-6145459-C-T

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.*160G>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 0.16 in 882,710 control chromosomes in the GnomAD database, including 12,607 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2723 hom., cov: 32)
  • Exomes 𝑓: 0.16 (9884 hom.)
• Consequence: F13A1 NM_000129.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.801

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-6145459-C-T is Benign according to our data. Variant chr6-6145459-C-T is described in ClinVar as [Benign]. Clinvar id is 357662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-6145459-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F13A1	NM_000129.4	c.*160G>A		3_prime_UTR_variant	15/15	ENST00000264870.8	NP_000120.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F13A1	ENST00000264870.8	c.*160G>A		3_prime_UTR_variant	15/15	1	NM_000129.4	ENSP00000264870	P1

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27309 AN: 152052 Hom.: 2706 Cov.: 32

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0878

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.182

GnomAD4 exome AF: 0.156 AC: 114230 AN: 730540 Hom.: 9884 Cov.: 10 AF XY: 0.153 AC XY: 58595 AN XY: 382342

Gnomad4 AFR exome AF: 0.251

Gnomad4 AMR exome AF: 0.166

Gnomad4 ASJ exome AF: 0.207

Gnomad4 EAS exome AF: 0.000270

Gnomad4 SAS exome AF: 0.0981

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.171

Gnomad4 OTH exome AF: 0.163

GnomAD4 genome AF: 0.180 AC: 27357 AN: 152170 Hom.: 2723 Cov.: 32 AF XY: 0.174 AC XY: 12935 AN XY: 74394

Gnomad4 AFR AF: 0.248

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.201

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.0877

Gnomad4 FIN AF: 0.129

Gnomad4 NFE AF: 0.170

Gnomad4 OTH AF: 0.180

Alfa AF: 0.173 Hom.: 3190

Bravo AF: 0.186

Asia WGS AF: 0.0520 AC: 184 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Factor XIII, A subunit, deficiency of Benign:1

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.50
DANN	Benign	0.31

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: rs1050783; hg19: chr6-6145692;