rs5983

Positions:

chr6-6167600-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000129.4(F13A1):c.1766T>A(p.Leu589Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00512 in 1,613,720 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 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 0.0043 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0052 ( 25 hom. )

Consequence

F13A1
NM_000129.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.179

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=0.014963478).

BP6

Variant 6-6167600-A-T is Benign according to our data. Variant chr6-6167600-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 786407.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=1}. Variant chr6-6167600-A-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00431 (656/152226) while in subpopulation NFE AF= 0.00622 (423/68016). AF 95% confidence interval is 0.00573. There are 9 homozygotes in gnomad4. There are 299 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F13A1	NM_000129.4 linkuse as main transcript	c.1766T>A	p.Leu589Gln	missense_variant	13/15	ENST00000264870.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F13A1	ENST00000264870.8 linkuse as main transcript	c.1766T>A	p.Leu589Gln	missense_variant	13/15	1	NM_000129.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00431

AC:

656

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00550

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00622

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00379

AC:

951

AN:

251142

Hom.:

AF XY:

0.00374

AC XY:

508

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00194

Gnomad ASJ exome

AF:

0.0103

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00154

Gnomad FIN exome

AF:

0.00134

Gnomad NFE exome

AF:

0.00581

Gnomad OTH exome

AF:

0.00392

GnomAD4 exome

AF:

0.00521

AC:

7609

AN:

1461494

Hom.:

Cov.:

AF XY:

0.00512

AC XY:

3725

AN XY:

727056

show subpopulations

Gnomad4 AFR exome

AF:

0.000837

Gnomad4 AMR exome

AF:

0.00188

Gnomad4 ASJ exome

AF:

0.0106

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00173

Gnomad4 FIN exome

AF:

0.00167

Gnomad4 NFE exome

AF:

0.00603

Gnomad4 OTH exome

AF:

0.00451

GnomAD4 genome

AF:

0.00431

AC:

656

AN:

152226

Hom.:

Cov.:

AF XY:

0.00402

AC XY:

299

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00145

Gnomad4 AMR

AF:

0.00549

Gnomad4 ASJ

AF:

0.0161

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00622

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00592

Hom.:

Bravo

AF:

0.00365

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00860

AC:

ExAC

AF:

0.00390

AC:

474

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00594

EpiControl

AF:

0.00575

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	F13A1: BP4, BS2 -

Factor XIII, A subunit, deficiency of

Uncertain:1

Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.47

CADD

Benign

0.53

DANN

Benign

0.59

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.080

M_CAP

Benign

0.014

MetaRNN

Benign

0.015

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.87

REVEL

Benign

0.062

Sift

Benign

0.63

Sift4G

Benign

0.62

Vest4

0.26

MVP

0.33

MPC

0.24

ClinPred

0.00055

GERP RS

-2.0

gMVP

0.72

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