1-197050849-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001994.3(F13B):c.1586T>C(p.Leu529Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,613,222 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0070 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (4 hom.)
• Consequence: F13B NM_001994.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.53

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072193444).
• BP6: Variant 1-197050849-A-G is Benign according to our data. Variant chr1-197050849-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 717817.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00705 (1073/152284) while in subpopulation AFR AF= 0.0234 (973/41578). AF 95% confidence interval is 0.0222. There are 10 homozygotes in gnomad4. There are 510 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F13B	NM_001994.3	c.1586T>C	p.Leu529Pro	missense_variant	10/12	ENST00000367412.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F13B	ENST00000367412.2	c.1586T>C	p.Leu529Pro	missense_variant	10/12	1	NM_001994.3	P1
F13B	ENST00000649282.1	c.341T>C	p.Leu114Pro	missense_variant	3/5
F13B	ENST00000490002.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00704 AC: 1071 AN: 152166 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00492

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00200 AC: 502 AN: 250582 Hom.: 3 AF XY: 0.00154 AC XY: 209 AN XY: 135418

Gnomad AFR exome AF: 0.0241

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000265

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.000810 AC: 1184 AN: 1460938 Hom.: 4 Cov.: 31 AF XY: 0.000715 AC XY: 520 AN XY: 726784

Gnomad4 AFR exome AF: 0.0215

Gnomad4 AMR exome AF: 0.00211

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000213

Gnomad4 OTH exome AF: 0.00201

GnomAD4 genome AF: 0.00705 AC: 1073 AN: 152284 Hom.: 10 Cov.: 32 AF XY: 0.00685 AC XY: 510 AN XY: 74452

Gnomad4 AFR AF: 0.0234

Gnomad4 AMR AF: 0.00491

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00193 Hom.: 3

Bravo AF: 0.00754

ESP6500AA AF: 0.0222 AC: 98

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00241 AC: 293

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Factor XIII, b subunit, deficiency of Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 09, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	16
Dann	Uncertain	0.99
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.48	T;T
MetaRNN	Benign	0.0072	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
Polyphen		0.28	.;B
Vest4		0.25
MVP		0.61
MPC		0.38
ClinPred		0.012	T
GERP RS		1.9
Varity_R		0.11
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs17549671; hg19: chr1-197019979;