NM_000129.4:c.1954G>C

Variant names:

• chr6-6151904-C-G
• rs5988
• NM_000129.4:c.1954G>C

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.1954G>C​(p.Glu652Gln) variant causes a missense change. The variant allele was found at a frequency of 0.223 in 1,613,450 control chromosomes in the GnomAD database, including 40,803 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3568 hom., cov: 32)
  • Exomes 𝑓: 0.22 (37235 hom.)
• Consequence: F13A1 NM_000129.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.73
• Publications: 30 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=0.005915642).
• BP6: Variant 6-6151904-C-G is Benign according to our data. Variant chr6-6151904-C-G is described in ClinVar as Benign. ClinVar VariationId is 255186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.225 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.1954G>C	p.Glu652Gln	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.1954G>C	p.Glu652Gln	missense	Exon 14 of 15	ENSP00000264870.3	P00488
	F13A1	ENST00000950947.1		c.1954G>C	p.Glu652Gln	missense	Exon 13 of 14	ENSP00000621006.1
	F13A1	ENST00000878383.1		c.1765G>C	p.Glu589Gln	missense	Exon 13 of 14	ENSP00000548442.1

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32466 AN: 151986 Hom.: 3560 Cov.: 32

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.261

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.225

GnomAD2 exomes AF: 0.209 AC: 52498 AN: 250854 AF XY: 0.211

Gnomad AFR exome AF: 0.207

Gnomad AMR exome AF: 0.205

Gnomad ASJ exome AF: 0.280

Gnomad EAS exome AF: 0.0965

Gnomad FIN exome AF: 0.181

Gnomad NFE exome AF: 0.227

Gnomad OTH exome AF: 0.223

GnomAD4 exome AF: 0.224 AC: 326671 AN: 1461346 Hom.: 37235 Cov.: 35 AF XY: 0.224 AC XY: 162579 AN XY: 727004

African (AFR) AF: 0.202 AC: 6755 AN: 33468

American (AMR) AF: 0.208 AC: 9284 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 7225 AN: 26128

East Asian (EAS) AF: 0.111 AC: 4407 AN: 39680

South Asian (SAS) AF: 0.212 AC: 18310 AN: 86242

European-Finnish (FIN) AF: 0.179 AC: 9564 AN: 53396

Middle Eastern (MID) AF: 0.298 AC: 1719 AN: 5764

European-Non Finnish (NFE) AF: 0.230 AC: 256120 AN: 1111600

Other (OTH) AF: 0.220 AC: 13287 AN: 60368

GnomAD4 genome AF: 0.214 AC: 32507 AN: 152104 Hom.: 3568 Cov.: 32 AF XY: 0.211 AC XY: 15694 AN XY: 74364

African (AFR) AF: 0.206 AC: 8531 AN: 41486

American (AMR) AF: 0.214 AC: 3267 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 918 AN: 3468

East Asian (EAS) AF: 0.102 AC: 529 AN: 5162

South Asian (SAS) AF: 0.210 AC: 1013 AN: 4826

European-Finnish (FIN) AF: 0.195 AC: 2064 AN: 10588

Middle Eastern (MID) AF: 0.271 AC: 79 AN: 292

European-Non Finnish (NFE) AF: 0.228 AC: 15514 AN: 67980

Other (OTH) AF: 0.225 AC: 474 AN: 2110

Alfa AF: 0.226 Hom.: 3035

Bravo AF: 0.212

TwinsUK AF: 0.231 AC: 856

ALSPAC AF: 0.239 AC: 923

ESP6500AA AF: 0.200 AC: 881

ESP6500EA AF: 0.233 AC: 2003

ExAC AF: 0.208 AC: 25293

Asia WGS AF: 0.144 AC: 505 AN: 3478

EpiCase AF: 0.236

EpiControl AF: 0.234

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Factor XIII, A subunit, deficiency of (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Uncertain	1.0
Eigen	Benign	0.12
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.89	D
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.89	T
PhyloP100		4.7
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.070
Sift	Benign	0.30	T
Sift4G	Benign	0.32	T
Vest4		0.21
MPC		0.25
ClinPred		0.012	T
GERP RS		4.5
gMVP		0.64
Mutation Taster		=79/21	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5988; hg19: chr6-6152137; COSMIC: COSV53559470;