1-197061071-T-C

Variant names:

• chr1-197061071-T-C
• rs5997
• NM_001994.3:c.456A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001994.3(F13B):​c.456A>G​(p.Thr152Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.884 in 1,456,352 control chromosomes in the GnomAD database, including 577,146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (50031 hom., cov: 32)
  • Exomes 𝑓: 0.90 (527115 hom.)
• Consequence: F13B NM_001994.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.914
• Publications: 16 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 1-197061071-T-C is Benign according to our data. Variant chr1-197061071-T-C is described in ClinVar as Benign. ClinVar VariationId is 258505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.914 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F13B	NM_001994.3	c.456A>G	p.Thr152Thr	synonymous_variant	Exon 4 of 12	ENST00000367412.2	NP_001985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F13B	ENST00000367412.2	c.456A>G	p.Thr152Thr	synonymous_variant	Exon 4 of 12	1	NM_001994.3	ENSP00000356382.2

Frequencies

GnomAD3 genomes AF: 0.785 AC: 119230 AN: 151866 Hom.: 50007 Cov.: 32

Gnomad AFR AF: 0.454

Gnomad AMI AF: 0.955

Gnomad AMR AF: 0.872

Gnomad ASJ AF: 0.902

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.898

Gnomad FIN AF: 0.929

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.910

Gnomad OTH AF: 0.815

GnomAD2 exomes AF: 0.890 AC: 206883 AN: 232354 AF XY: 0.896

Gnomad AFR exome AF: 0.453

Gnomad AMR exome AF: 0.938

Gnomad ASJ exome AF: 0.896

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.931

Gnomad NFE exome AF: 0.907

Gnomad OTH exome AF: 0.902

GnomAD4 exome AF: 0.896 AC: 1168190 AN: 1304366 Hom.: 527115 Cov.: 19 AF XY: 0.897 AC XY: 585401 AN XY: 652506

African (AFR) AF: 0.435 AC: 13207 AN: 30352

American (AMR) AF: 0.931 AC: 38898 AN: 41760

Ashkenazi Jewish (ASJ) AF: 0.901 AC: 21862 AN: 24256

East Asian (EAS) AF: 1.00 AC: 37584 AN: 37594

South Asian (SAS) AF: 0.901 AC: 63806 AN: 70844

European-Finnish (FIN) AF: 0.932 AC: 47352 AN: 50786

Middle Eastern (MID) AF: 0.869 AC: 4653 AN: 5352

European-Non Finnish (NFE) AF: 0.903 AC: 892852 AN: 989070

Other (OTH) AF: 0.883 AC: 47976 AN: 54352

GnomAD4 genome AF: 0.785 AC: 119306 AN: 151986 Hom.: 50031 Cov.: 32 AF XY: 0.790 AC XY: 58677 AN XY: 74304

African (AFR) AF: 0.455 AC: 18840 AN: 41430

American (AMR) AF: 0.872 AC: 13308 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.902 AC: 3133 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5182 AN: 5186

South Asian (SAS) AF: 0.899 AC: 4341 AN: 4828

European-Finnish (FIN) AF: 0.929 AC: 9799 AN: 10550

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.910 AC: 61845 AN: 67946

Other (OTH) AF: 0.817 AC: 1722 AN: 2108

Alfa AF: 0.852 Hom.: 27431

Bravo AF: 0.767

Asia WGS AF: 0.920 AC: 3195 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Factor XIII, b subunit, deficiency of Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.85
DANN	Benign	0.67
PhyloP100		-0.91
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5997; hg19: chr1-197030201;