rs5983

Positions:

• chr6-6167600-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.179

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=0.014963478).
• 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: {Likely_benign=1, Uncertain_significance=1, Benign=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	Protein	UniProt
F13A1	NM_000129.4	c.1766T>A	p.Leu589Gln	missense_variant	13/15	ENST00000264870.8	NP_000120.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F13A1	ENST00000264870.8	c.1766T>A	p.Leu589Gln	missense_variant	13/15	1	NM_000129.4	ENSP00000264870.3

Frequencies

GnomAD3 genomes AF: 0.00431 AC: 656 AN: 152108 Hom.: 9 Cov.: 32

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.: 2 AF XY: 0.00374 AC XY: 508 AN XY: 135756

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.: 25 Cov.: 32 AF XY: 0.00512 AC XY: 3725 AN XY: 727056

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.: 9 Cov.: 32 AF XY: 0.00402 AC XY: 299 AN XY: 74432

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.: 2

Bravo AF: 0.00365

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00860 AC: 74

ExAC AF: 0.00390 AC: 474

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00594

EpiControl AF: 0.00575

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

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

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	T
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	N
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.062
Sift	Benign	0.63	T
Sift4G	Benign	0.62	T
Vest4		0.26
MVP		0.33
MPC		0.24
ClinPred		0.00055	T
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

Other links and lift over

dbSNP: rs5983; hg19: chr6-6167833;