rs5987

Variant names:

• chr6-6151907-C-T
• rs5987
• NM_000129.4:c.1951G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000129.4(F13A1):​c.1951G>A​(p.Val651Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.06 in 1,613,824 control chromosomes in the GnomAD database, including 3,289 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (292 hom., cov: 33)
  • Exomes 𝑓: 0.061 (2997 hom.)
• Consequence: F13A1 NM_000129.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.69
• Publications: 22 publications found

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 Gene-Disease associations (from GenCC):

• factor XIII, A subunit, deficiency of

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen
• congenital factor XIII deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002224654).
• BP6: Variant 6-6151907-C-T is Benign according to our data. Variant chr6-6151907-C-T is described in ClinVar as Benign. ClinVar VariationId is 255185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000129.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F13A1	NM_000129.4	MANE Select	c.1951G>A	p.Val651Ile	missense	Exon 14 of 15	NP_000120.2	P00488

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F13A1	ENST00000264870.8	TSL:1 MANE Select	c.1951G>A	p.Val651Ile	missense	Exon 14 of 15	ENSP00000264870.3	P00488
	F13A1	ENST00000950947.1		c.1951G>A	p.Val651Ile	missense	Exon 13 of 14	ENSP00000621006.1
	F13A1	ENST00000878383.1		c.1762G>A	p.Val588Ile	missense	Exon 13 of 14	ENSP00000548442.1

Frequencies

GnomAD3 genomes AF: 0.0552 AC: 8397 AN: 152120 Hom.: 292 Cov.: 33

Gnomad AFR AF: 0.0359

Gnomad AMI AF: 0.0615

Gnomad AMR AF: 0.0583

Gnomad ASJ AF: 0.0631

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0639

Gnomad MID AF: 0.0892

Gnomad NFE AF: 0.0562

Gnomad OTH AF: 0.0574

GnomAD2 exomes AF: 0.0659 AC: 16537 AN: 250912 AF XY: 0.0698

Gnomad AFR exome AF: 0.0355

Gnomad AMR exome AF: 0.0465

Gnomad ASJ exome AF: 0.0704

Gnomad EAS exome AF: 0.0956

Gnomad FIN exome AF: 0.0588

Gnomad NFE exome AF: 0.0582

Gnomad OTH exome AF: 0.0655

GnomAD4 exome AF: 0.0605 AC: 88496 AN: 1461586 Hom.: 2997 Cov.: 34 AF XY: 0.0623 AC XY: 45289 AN XY: 727104

African (AFR) AF: 0.0362 AC: 1211 AN: 33470

American (AMR) AF: 0.0468 AC: 2090 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0683 AC: 1784 AN: 26134

East Asian (EAS) AF: 0.111 AC: 4389 AN: 39676

South Asian (SAS) AF: 0.116 AC: 9987 AN: 86246

European-Finnish (FIN) AF: 0.0577 AC: 3084 AN: 53410

Middle Eastern (MID) AF: 0.0898 AC: 518 AN: 5766

European-Non Finnish (NFE) AF: 0.0556 AC: 61794 AN: 1111798

Other (OTH) AF: 0.0603 AC: 3639 AN: 60384

GnomAD4 genome AF: 0.0552 AC: 8401 AN: 152238 Hom.: 292 Cov.: 33 AF XY: 0.0576 AC XY: 4287 AN XY: 74424

African (AFR) AF: 0.0359 AC: 1490 AN: 41550

American (AMR) AF: 0.0582 AC: 890 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0631 AC: 219 AN: 3470

East Asian (EAS) AF: 0.100 AC: 518 AN: 5158

South Asian (SAS) AF: 0.119 AC: 576 AN: 4822

European-Finnish (FIN) AF: 0.0639 AC: 679 AN: 10618

Middle Eastern (MID) AF: 0.0959 AC: 28 AN: 292

European-Non Finnish (NFE) AF: 0.0562 AC: 3821 AN: 68016

Other (OTH) AF: 0.0587 AC: 124 AN: 2114

Alfa AF: 0.0559 Hom.: 438

Bravo AF: 0.0522

TwinsUK AF: 0.0483 AC: 179

ALSPAC AF: 0.0594 AC: 229

ESP6500AA AF: 0.0304 AC: 134

ESP6500EA AF: 0.0593 AC: 510

ExAC AF: 0.0675 AC: 8195

Asia WGS AF: 0.0960 AC: 334 AN: 3478

EpiCase AF: 0.0630

EpiControl AF: 0.0620

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Factor XIII, A subunit, deficiency of (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Benign	0.49
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.056
FATHMM_MKL	Benign	0.48	N
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.7
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.16
Sift	Benign	0.87	T
Sift4G	Benign	0.84	T
Vest4		0.18
MPC		0.18
ClinPred		0.023	T
GERP RS		5.4
gMVP		0.47
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5987; hg19: chr6-6152140; COSMIC: COSV53559477;