chr6-6145032-C-T

Position:

• chr6-6145032-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting 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

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 -7 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F13A1	NM_000129.4	c.*587G>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.*587G>A		3_prime_UTR_variant	15/15	1	NM_000129.4	ENSP00000264870	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00385

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00331

Gnomad4 FIN exome AF: 0.0305

Gnomad4 NFE exome AF: 0.00950

Gnomad4 OTH exome AF: 0.0197

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

Gnomad4 AFR AF: 0.00209

Gnomad4 AMR AF: 0.00968

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.0153

Gnomad4 NFE AF: 0.0118

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0112 Hom.: 2

Bravo AF: 0.00756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Factor XIII, A subunit, deficiency of Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.4
DANN	Benign	0.63

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: rs75981686; hg19: chr6-6145265;