1-197052684-G-C

Variant names:

• chr1-197052684-G-C
• rs928709083
• NM_001994.3:c.1505C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001994.3(F13B):​c.1505C>G​(p.Ser502Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: F13B NM_001994.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.14
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• congenital factor XIII deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-197052684-G-C is Pathogenic according to our data. Variant chr1-197052684-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1322006.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19935325). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F13B	NM_001994.3	c.1505C>G	p.Ser502Cys	missense_variant	Exon 9 of 12	ENST00000367412.2	NP_001985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F13B	ENST00000367412.2	c.1505C>G	p.Ser502Cys	missense_variant	Exon 9 of 12	1	NM_001994.3	ENSP00000356382.2
F13B	ENST00000649282.1	c.260C>G	p.Ser87Cys	missense_variant	Exon 2 of 5			ENSP00000497116.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cholesteatoma Pathogenic:1

-

Phenosystems SA

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.48	.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.70	T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.2	.;M
PhyloP100		1.1
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.8	.;N
REVEL	Benign	0.24
Sift	Benign	0.045	.;D
Sift4G	Uncertain	0.060	.;T
Polyphen		0.93	.;P
Vest4		0.28
MutPred		0.40		.;Loss of disorder (P = 0.038);
MVP		0.83
MPC		0.44
ClinPred		0.46	T
GERP RS		3.5
Varity_R		0.081
gMVP		0.61
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs928709083; hg19: chr1-197021814;