rs5982

chr6-6174633-G-Achr6-6174633-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000129.4(F13A1):c.1694C>T(p.Pro565Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 1,613,906 control chromosomes in the GnomAD database, including 38,795 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P565P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.20 (3094 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35701 hom.)
• Consequence: F13A1 NM_000129.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.58

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069898665).
• BP6: Variant 6-6174633-G-A is Benign according to our data. Variant chr6-6174633-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255183.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=4}. Variant chr6-6174633-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F13A1	NM_000129.4	c.1694C>T	p.Pro565Leu	missense_variant	12/15	ENST00000264870.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F13A1	ENST00000264870.8	c.1694C>T	p.Pro565Leu	missense_variant	12/15	1	NM_000129.4	P1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29762 AN: 151976 Hom.: 3090 Cov.: 32

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.196

GnomAD3 exomes AF: 0.212 AC: 53317 AN: 251446 Hom.: 6330 AF XY: 0.223 AC XY: 30301 AN XY: 135894

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.0951

Gnomad ASJ exome AF: 0.224

Gnomad EAS exome AF: 0.321

Gnomad SAS exome AF: 0.334

Gnomad FIN exome AF: 0.207

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.207

GnomAD4 exome AF: 0.216 AC: 315131 AN: 1461812 Hom.: 35701 Cov.: 40 AF XY: 0.219 AC XY: 159585 AN XY: 727206

Gnomad4 AFR exome AF: 0.154

Gnomad4 AMR exome AF: 0.101

Gnomad4 ASJ exome AF: 0.221

Gnomad4 EAS exome AF: 0.302

Gnomad4 SAS exome AF: 0.328

Gnomad4 FIN exome AF: 0.203

Gnomad4 NFE exome AF: 0.210

Gnomad4 OTH exome AF: 0.225

GnomAD4 genome AF: 0.196 AC: 29785 AN: 152094 Hom.: 3094 Cov.: 32 AF XY: 0.199 AC XY: 14758 AN XY: 74342

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.135

Gnomad4 ASJ AF: 0.219

Gnomad4 EAS AF: 0.306

Gnomad4 SAS AF: 0.348

Gnomad4 FIN AF: 0.213

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.196

Alfa AF: 0.205 Hom.: 5455

Bravo AF: 0.182

TwinsUK AF: 0.210 AC: 777

ALSPAC AF: 0.198 AC: 765

ESP6500AA AF: 0.158 AC: 697

ESP6500EA AF: 0.210 AC: 1807

ExAC AF: 0.216 AC: 26217

Asia WGS AF: 0.281 AC: 978 AN: 3478

EpiCase AF: 0.212

EpiControl AF: 0.213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 9920838, 11108652, 20384622) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -

Factor XIII, A subunit, deficiency of Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	20
Dann	Benign	0.38
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.45	N
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.077
Sift	Benign	0.73	T
Sift4G	Benign	0.67	T
Vest4		0.036
MPC		0.23
ClinPred		0.012	T
GERP RS		5.8
gMVP		0.58

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: rs5982; hg19: chr6-6174866; COSMIC: COSV53555780;