NM_001994.3:c.344G>A

Variant names:

• chr1-197061891-C-T
• rs6003
• NM_001994.3:c.344G>A

Variant summary

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

The NM_001994.3(F13B):​c.344G>A​(p.Arg115His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.883 in 1,612,650 control chromosomes in the GnomAD database, including 638,098 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (48909 hom., cov: 30)
  • Exomes 𝑓: 0.89 (589189 hom.)
• Consequence: F13B NM_001994.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.438
• Publications: 77 publications found

Genes affected

F13B (HGNC:3534): (coagulation factor XIII B chain) This gene encodes coagulation factor XIII B 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 a plasma carrier molecules. Platelet factor XIII is comprised only of 2 A subunits, which are identical to those of plasma origin. Upon activation by the 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. 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]

F13B Gene-Disease associations (from GenCC):

• factor XIII, b subunit, deficiency of

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, 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=6.8317645E-6).
• BP6: Variant 1-197061891-C-T is Benign according to our data. Variant chr1-197061891-C-T is described in ClinVar as Benign. ClinVar VariationId is 16520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001994.3. 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
	F13B	NM_001994.3	MANE Select	c.344G>A	p.Arg115His	missense	Exon 3 of 12	NP_001985.2	P05160

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F13B	ENST00000367412.2	TSL:1 MANE Select	c.344G>A	p.Arg115His	missense	Exon 3 of 12	ENSP00000356382.2	P05160
	F13B	ENST00000895404.1		c.344G>A	p.Arg115His	missense	Exon 3 of 11	ENSP00000565463.1
	F13B	ENST00000895399.1		c.344G>A	p.Arg115His	missense	Exon 3 of 11	ENSP00000565458.1

Frequencies

GnomAD3 genomes AF: 0.770 AC: 116834 AN: 151792 Hom.: 48890 Cov.: 30

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.955

Gnomad AMR AF: 0.868

Gnomad ASJ AF: 0.902

Gnomad EAS AF: 0.979

Gnomad SAS AF: 0.896

Gnomad FIN AF: 0.929

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.910

Gnomad OTH AF: 0.800

GnomAD2 exomes AF: 0.882 AC: 220834 AN: 250328 AF XY: 0.890

Gnomad AFR exome AF: 0.391

Gnomad AMR exome AF: 0.932

Gnomad ASJ exome AF: 0.894

Gnomad EAS exome AF: 0.982

Gnomad FIN exome AF: 0.930

Gnomad NFE exome AF: 0.906

Gnomad OTH exome AF: 0.897

GnomAD4 exome AF: 0.894 AC: 1306317 AN: 1460740 Hom.: 589189 Cov.: 43 AF XY: 0.896 AC XY: 651004 AN XY: 726666

African (AFR) AF: 0.382 AC: 12776 AN: 33430

American (AMR) AF: 0.927 AC: 41338 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.900 AC: 23506 AN: 26112

East Asian (EAS) AF: 0.982 AC: 38919 AN: 39628

South Asian (SAS) AF: 0.898 AC: 77407 AN: 86234

European-Finnish (FIN) AF: 0.932 AC: 49739 AN: 53362

Middle Eastern (MID) AF: 0.866 AC: 4985 AN: 5758

European-Non Finnish (NFE) AF: 0.904 AC: 1004608 AN: 1111292

Other (OTH) AF: 0.879 AC: 53039 AN: 60322

GnomAD4 genome AF: 0.770 AC: 116902 AN: 151910 Hom.: 48909 Cov.: 30 AF XY: 0.775 AC XY: 57553 AN XY: 74276

African (AFR) AF: 0.403 AC: 16673 AN: 41378

American (AMR) AF: 0.868 AC: 13237 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.902 AC: 3131 AN: 3470

East Asian (EAS) AF: 0.979 AC: 5052 AN: 5162

South Asian (SAS) AF: 0.897 AC: 4314 AN: 4812

European-Finnish (FIN) AF: 0.929 AC: 9842 AN: 10592

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.910 AC: 61830 AN: 67942

Other (OTH) AF: 0.802 AC: 1688 AN: 2104

Alfa AF: 0.871 Hom.: 285990

Bravo AF: 0.749

ESP6500AA AF: 0.409 AC: 1804

ESP6500EA AF: 0.907 AC: 7801

ExAC AF: 0.872 AC: 105765

Asia WGS AF: 0.911 AC: 3166 AN: 3476

EpiCase AF: 0.905

EpiControl AF: 0.909

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Factor XIII, b subunit, deficiency of (2)
-	-	2	not provided (2)
-	-	-	Venous thrombosis, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.64
DANN	Benign	0.31
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0000068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.79	N
PhyloP100		-0.44
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.037
Sift	Benign	0.38	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.018
MPC		0.16
ClinPred		0.0072	T
GERP RS		-0.82
Varity_R		0.032
gMVP		0.59
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6003; hg19: chr1-197031021; COSMIC: COSV107470722;