chr6-6145176-C-T

Position:

• chr6-6145176-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.*443G>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 0.0497 in 215,478 control chromosomes in the GnomAD database, including 374 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (239 hom., cov: 32)
  • Exomes 𝑓: 0.055 (135 hom.)
• Consequence: F13A1 NM_000129.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.645

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=-0.86).
• BP6: Variant 6-6145176-C-T is Benign according to our data. Variant chr6-6145176-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 357658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0688 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F13A1	NM_000129.4	c.*443G>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.*443G>A		3_prime_UTR_variant	15/15	1	NM_000129.4	ENSP00000264870	P1

Frequencies

GnomAD3 genomes AF: 0.0477 AC: 7248 AN: 151996 Hom.: 238 Cov.: 32

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.0492

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.0197

Gnomad SAS AF: 0.0260

Gnomad FIN AF: 0.0548

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0705

Gnomad OTH AF: 0.0561

GnomAD4 exome AF: 0.0547 AC: 3463 AN: 63364 Hom.: 135 Cov.: 0 AF XY: 0.0522 AC XY: 1756 AN XY: 33670

Gnomad4 AFR exome AF: 0.00917

Gnomad4 AMR exome AF: 0.0313

Gnomad4 ASJ exome AF: 0.0410

Gnomad4 EAS exome AF: 0.0190

Gnomad4 SAS exome AF: 0.0277

Gnomad4 FIN exome AF: 0.0601

Gnomad4 NFE exome AF: 0.0672

Gnomad4 OTH exome AF: 0.0580

GnomAD4 genome AF: 0.0476 AC: 7245 AN: 152114 Hom.: 239 Cov.: 32 AF XY: 0.0459 AC XY: 3412 AN XY: 74344

Gnomad4 AFR AF: 0.0125

Gnomad4 AMR AF: 0.0491

Gnomad4 ASJ AF: 0.0493

Gnomad4 EAS AF: 0.0197

Gnomad4 SAS AF: 0.0260

Gnomad4 FIN AF: 0.0548

Gnomad4 NFE AF: 0.0705

Gnomad4 OTH AF: 0.0555

Alfa AF: 0.0652 Hom.: 468

Bravo AF: 0.0471

Asia WGS AF: 0.0240 AC: 83 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Factor XIII, A subunit, deficiency of Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.4
DANN	Benign	0.30

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: rs3024486; hg19: chr6-6145409;