rs3024477

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000129.4(F13A1):c.614A>T(p.Tyr205Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0249 in 1,613,014 control chromosomes in the GnomAD database, including 609 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 40 hom., cov: 33)

Exomes 𝑓: 0.026 ( 569 hom. )

Consequence

F13A1
NM_000129.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.44

Variant links:

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 links:

F13A1 (HGNC:):

F13A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010353804).

BP6

Variant 6-6250887-T-A is Benign according to our data. Variant chr6-6250887-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 908780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0186 (2840/152300) while in subpopulation NFE AF= 0.0292 (1985/68018). AF 95% confidence interval is 0.0281. There are 40 homozygotes in gnomad4. There are 1373 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F13A1	NM_000129.4 linkuse as main transcript	c.614A>T	p.Tyr205Phe	missense_variant	5/15	ENST00000264870.8	NP_000120.2	P00488

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F13A1	ENST00000264870.8 linkuse as main transcript	c.614A>T	p.Tyr205Phe	missense_variant	5/15	1	NM_000129.4	ENSP00000264870.3		P00488
F13A1	ENST00000479211.1 linkuse as main transcript	n.*20A>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0187

AC:

2841

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00540

Gnomad AMI

AF:

0.0526

Gnomad AMR

AF:

0.00668

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0364

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0292

Gnomad OTH

AF:

0.00956

GnomAD3 exomes

AF:

0.0179

AC:

4499

AN:

251072

Hom.:

AF XY:

0.0176

AC XY:

2384

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.00461

Gnomad AMR exome

AF:

0.00613

Gnomad ASJ exome

AF:

0.0208

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00287

Gnomad FIN exome

AF:

0.0352

Gnomad NFE exome

AF:

0.0269

Gnomad OTH exome

AF:

0.0162

GnomAD4 exome

AF:

0.0256

AC:

37325

AN:

1460714

Hom.:

569

Cov.:

AF XY:

0.0248

AC XY:

18015

AN XY:

726714

show subpopulations

Gnomad4 AFR exome

AF:

0.00376

Gnomad4 AMR exome

AF:

0.00704

Gnomad4 ASJ exome

AF:

0.0203

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00325

Gnomad4 FIN exome

AF:

0.0356

Gnomad4 NFE exome

AF:

0.0296

Gnomad4 OTH exome

AF:

0.0219

GnomAD4 genome

AF:

0.0186

AC:

2840

AN:

152300

Hom.:

Cov.:

AF XY:

0.0184

AC XY:

1373

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00539

Gnomad4 AMR

AF:

0.00660

Gnomad4 ASJ

AF:

0.0173

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.0364

Gnomad4 NFE

AF:

0.0292

Gnomad4 OTH

AF:

0.00946

Alfa

AF:

0.0239

Hom.:

Bravo

AF:

0.0161

TwinsUK

AF:

0.0318

AC:

118

ALSPAC

AF:

0.0267

AC:

103

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.0279

AC:

240

ExAC

AF:

0.0172

AC:

2083

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0264

EpiControl

AF:

0.0254

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Factor XIII, A subunit, deficiency of

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.98

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.92

MetaRNN

Benign

0.010

MetaSVM

Pathogenic

0.81

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.58

Sift

Benign

0.056

Sift4G

Benign

0.21

Vest4

0.26

MPC

0.72

ClinPred

0.025

GERP RS

4.7

gMVP

0.34

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over