1-197040539-T-A

Variant names:

• chr1-197040539-T-A
• rs149091258
• NM_001994.3:c.1935A>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001994.3(F13B):​c.1935A>T​(p.Arg645Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,610,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000093 (0 hom.)
• Consequence: F13B NM_001994.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 B:1
• Conservation: PhyloP100: -0.320
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011920601).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000935 (142/151932) while in subpopulation AFR AF = 0.00328 (136/41484). AF 95% confidence interval is 0.00283. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1935A>T	p.Arg645Ser	missense	Exon 11 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.1935A>T	p.Arg645Ser	missense	Exon 11 of 12	ENSP00000356382.2	P05160
	F13B	ENST00000895404.1		c.1752A>T	p.Arg584Ser	missense	Exon 10 of 11	ENSP00000565463.1
	F13B	ENST00000895399.1		c.1734A>T	p.Arg578Ser	missense	Exon 10 of 11	ENSP00000565458.1

Frequencies

GnomAD3 genomes AF: 0.000935 AC: 142 AN: 151816 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000180 AC: 45 AN: 250576 AF XY: 0.000155

Gnomad AFR exome AF: 0.00251

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000933 AC: 136 AN: 1458364 Hom.: 0 Cov.: 33 AF XY: 0.0000661 AC XY: 48 AN XY: 725638

African (AFR) AF: 0.00348 AC: 116 AN: 33376

American (AMR) AF: 0.000179 AC: 8 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 86112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5310

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1109566

Other (OTH) AF: 0.000133 AC: 8 AN: 60224

GnomAD4 genome AF: 0.000935 AC: 142 AN: 151932 Hom.: 0 Cov.: 32 AF XY: 0.000956 AC XY: 71 AN XY: 74278

African (AFR) AF: 0.00328 AC: 136 AN: 41484

American (AMR) AF: 0.000328 AC: 5 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67892

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000224 Hom.: 0

Bravo AF: 0.00127

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000198 AC: 24

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	F13B-related disorder (1)
-	1	-	Factor XIII, b subunit, deficiency of (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Benign	0.90
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.32
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.15
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.023	D
Polyphen		0.32	B
Vest4		0.36
MutPred		0.46		Loss of MoRF binding (P = 0.0138)
MVP		0.72
MPC		0.20
ClinPred		0.042	T
GERP RS		-4.4
Varity_R		0.13
gMVP		0.46
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs149091258; hg19: chr1-197009669;