6-6174633-G-A

Position:

chr6-6174633-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

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. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.20 ( 3094 hom., cov: 32)

Exomes 𝑓: 0.22 ( 35701 hom. )

Consequence

F13A1
NM_000129.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 2.58

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
F13A1	NM_000129.4 linkuse as main transcript	c.1694C>T	p.Pro565Leu	missense_variant	12/15	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.1694C>T	p.Pro565Leu	missense_variant	12/15	1	NM_000129.4	ENSP00000264870.3		P00488

Frequencies

GnomAD3 genomes

AF:

0.196

AC:

29762

AN:

151976

Hom.:

3090

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.219

AC XY:

159585

AN XY:

727206

show subpopulations

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.:

AF XY:

0.199

AC XY:

14758

AN XY:

74342

show subpopulations

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:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

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

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.38

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.45

MetaRNN

Benign

0.0070

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.35

PROVEAN

Benign

0.31

REVEL

Benign

0.077

Sift

Benign

0.73

Sift4G

Benign

0.67

Vest4

0.036

MPC

0.23

ClinPred

0.012

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

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