rs6000

chr1-197050728-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001994.3(F13B):c.1707T>G(p.Asp569Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00337 in 1,613,206 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (53 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (56 hom.)
• Consequence: F13B NM_001994.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -6.02

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005678028).
• BP6: Variant 1-197050728-A-C is Benign according to our data. Variant chr1-197050728-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 294572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0151 (2303/152200) while in subpopulation AFR AF= 0.0491 (2041/41548). AF 95% confidence interval is 0.0473. There are 53 homozygotes in gnomad4. There are 1110 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 53 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F13B	NM_001994.3	c.1707T>G	p.Asp569Glu	missense_variant	10/12	ENST00000367412.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F13B	ENST00000367412.2	c.1707T>G	p.Asp569Glu	missense_variant	10/12	1	NM_001994.3	P1
F13B	ENST00000649282.1	c.462T>G	p.Asp154Glu	missense_variant	3/5
F13B	ENST00000490002.1	n.118T>G		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2298 AN: 152082 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.0491

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00683

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0202

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.00911

GnomAD3 exomes AF: 0.00528 AC: 1325 AN: 250800 Hom.: 23 AF XY: 0.00409 AC XY: 554 AN XY: 135538

Gnomad AFR exome AF: 0.0496

Gnomad AMR exome AF: 0.00320

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0178

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00215 AC: 3138 AN: 1461006 Hom.: 56 Cov.: 31 AF XY: 0.00198 AC XY: 1437 AN XY: 726828

Gnomad4 AFR exome AF: 0.0495

Gnomad4 AMR exome AF: 0.00323

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0176

Gnomad4 SAS exome AF: 0.000904

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000222

Gnomad4 OTH exome AF: 0.00496

GnomAD4 genome AF: 0.0151 AC: 2303 AN: 152200 Hom.: 53 Cov.: 32 AF XY: 0.0149 AC XY: 1110 AN XY: 74414

Gnomad4 AFR AF: 0.0491

Gnomad4 AMR AF: 0.00682

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0200

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000324

Gnomad4 OTH AF: 0.00901

Alfa AF: 0.00321 Hom.: 20

Bravo AF: 0.0162

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0481 AC: 212

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00602 AC: 731

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Factor XIII, b subunit, deficiency of Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.013
Dann	Benign	0.27
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.062	T;T
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
Polyphen		0.0010	.;B
Vest4		0.10
MutPred		0.44		.;Gain of phosphorylation at Y566 (P = 0.09);
MVP		0.42
MPC		0.12
ClinPred		0.97	D
GERP RS		-9.0
Varity_R		0.037
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6000; hg19: chr1-197019858;