rs5985

Positions:

Variant summary

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

The NM_000129.4(F13A1):c.103G>T(p.Val35Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,613,256 control chromosomes in the GnomAD database, including 46,576 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 0.22 ( 3785 hom., cov: 31)

Exomes 𝑓: 0.23 ( 42791 hom. )

Consequence

F13A1
NM_000129.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.148

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:

LOC124901253 (HGNC:):

LOC124901253 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=0.0058254898).

BP6

Variant 6-6318562-C-A is Benign according to our data. Variant chr6-6318562-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16532.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}. Variant chr6-6318562-C-A is described in Lovd as [Likely_benign]. Variant chr6-6318562-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.253 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.103G>T	p.Val35Leu	missense_variant	2/15	ENST00000264870.8	NP_000120.2
LOC124901253	XR_007059428.1 linkuse as main transcript	n.55-11191C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
F13A1	ENST00000264870.8 linkuse as main transcript	c.103G>T	p.Val35Leu	missense_variant	2/15	1	NM_000129.4	ENSP00000264870	P1
F13A1	ENST00000431222.6 linkuse as main transcript	c.265G>T	p.Val89Leu	missense_variant	3/5	4		ENSP00000416295
F13A1	ENST00000451619.1 linkuse as main transcript	c.178G>T	p.Val60Leu	missense_variant	2/3	2		ENSP00000411114
F13A1	ENST00000414279.5 linkuse as main transcript	c.103G>T	p.Val35Leu	missense_variant	3/5	4		ENSP00000413334

Frequencies

GnomAD3 genomes

AF:

0.215

AC:

32635

AN:

151822

Hom.:

3781

Cov.:

show subpopulations

Gnomad AFR

AF:

0.184

Gnomad AMI

AF:

0.372

Gnomad AMR

AF:

0.231

Gnomad ASJ

AF:

0.170

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.115

Gnomad FIN

AF:

0.206

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.256

Gnomad OTH

AF:

0.210

GnomAD3 exomes

AF:

0.205

AC:

51336

AN:

250876

Hom.:

5981

AF XY:

0.199

AC XY:

27046

AN XY:

135594

show subpopulations

Gnomad AFR exome

AF:

0.184

Gnomad AMR exome

AF:

0.255

Gnomad ASJ exome

AF:

0.170

Gnomad EAS exome

AF:

0.000926

Gnomad SAS exome

AF:

0.113

Gnomad FIN exome

AF:

0.200

Gnomad NFE exome

AF:

0.253

Gnomad OTH exome

AF:

0.212

GnomAD4 exome

AF:

0.235

AC:

343358

AN:

1461316

Hom.:

42791

Cov.:

AF XY:

0.231

AC XY:

168144

AN XY:

726956

show subpopulations

Gnomad4 AFR exome

AF:

0.180

Gnomad4 AMR exome

AF:

0.254

Gnomad4 ASJ exome

AF:

0.170

Gnomad4 EAS exome

AF:

0.000756

Gnomad4 SAS exome

AF:

0.116

Gnomad4 FIN exome

AF:

0.207

Gnomad4 NFE exome

AF:

0.258

Gnomad4 OTH exome

AF:

0.212

GnomAD4 genome

AF:

0.215

AC:

32673

AN:

151940

Hom.:

3785

Cov.:

AF XY:

0.210

AC XY:

15580

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.184

Gnomad4 AMR

AF:

0.230

Gnomad4 ASJ

AF:

0.170

Gnomad4 EAS

AF:

0.00232

Gnomad4 SAS

AF:

0.117

Gnomad4 FIN

AF:

0.206

Gnomad4 NFE

AF:

0.256

Gnomad4 OTH

AF:

0.207

Alfa

AF:

0.231

Hom.:

10452

Bravo

AF:

0.217

TwinsUK

AF:

0.256

AC:

950

ALSPAC

AF:

0.241

AC:

929

ESP6500AA

AF:

0.182

AC:

804

ESP6500EA

AF:

0.252

AC:

2163

ExAC

AF:

0.206

AC:

24994

Asia WGS

AF:

0.0640

AC:

225

AN:

3478

EpiCase

AF:

0.240

EpiControl

AF:

0.236

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	This variant is associated with the following publications: (PMID: 26035561, 25693916, 23314382, 27821352, 9459313, 22909824, 17568659, 9798996, 21800001, 19652888, 17899444, 19123042, 18808204, 22385348, 23677728, 9920838, 12456499, 24686102) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Myocardial infarction, protection against

Benign:1

protective, no assertion criteria provided

literature only

OMIM

Apr 01, 2007

- -

Venous thrombosis, protection against

Benign:1

protective, no assertion criteria provided

literature only

OMIM

Apr 01, 2007

- -

Factor XIII, A subunit, deficiency of

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.015

DANN

Benign

0.36

DEOGEN2

Benign

0.0065

.;.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.30

.;T;T

MetaRNN

Benign

0.0058

T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.27

N;N;N

REVEL

Benign

0.22

Sift

Benign

1.0

T;T;D

Sift4G

Benign

0.43

T;.;.

Vest4

0.018

MutPred

0.52

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;

MPC

0.22

ClinPred

0.00055

GERP RS

1.9

gMVP

0.25

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