1-197040378-G-C

Variant names:

• chr1-197040378-G-C
• rs12134960
• NM_001994.3:c.1952+144C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BA1

The NM_001994.3(F13B):​c.1952+144C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 622,928 control chromosomes in the GnomAD database, including 20,004 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3843 hom., cov: 32)
  • Exomes 𝑓: 0.22 (16161 hom.)
• Consequence: F13B NM_001994.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0480
• Publications: 12 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 -14 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 1-197040378-G-C is Benign according to our data. Variant chr1-197040378-G-C is described in ClinVar as [Benign]. Clinvar id is 1245718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F13B	NM_001994.3	c.1952+144C>G		intron_variant	Intron 11 of 11	ENST00000367412.2	NP_001985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F13B	ENST00000367412.2	c.1952+144C>G		intron_variant	Intron 11 of 11	1	NM_001994.3	ENSP00000356382.2
F13B	ENST00000649282.1	c.707+144C>G		intron_variant	Intron 4 of 4			ENSP00000497116.1
F13B	ENST00000490002.1	n.364-1C>G		splice_acceptor_variant, intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26643 AN: 151442 Hom.: 3835 Cov.: 32

Gnomad AFR AF: 0.0441

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.691

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.252

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.190

GnomAD4 exome AF: 0.218 AC: 102610 AN: 471374 Hom.: 16161 Cov.: 5 AF XY: 0.219 AC XY: 55329 AN XY: 252236

African (AFR) AF: 0.0407 AC: 506 AN: 12444

American (AMR) AF: 0.400 AC: 7306 AN: 18252

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 2576 AN: 14644

East Asian (EAS) AF: 0.678 AC: 20584 AN: 30374

South Asian (SAS) AF: 0.279 AC: 11605 AN: 41564

European-Finnish (FIN) AF: 0.240 AC: 8544 AN: 35674

Middle Eastern (MID) AF: 0.124 AC: 249 AN: 2014

European-Non Finnish (NFE) AF: 0.157 AC: 45646 AN: 290020

Other (OTH) AF: 0.212 AC: 5594 AN: 26388

GnomAD4 genome AF: 0.176 AC: 26654 AN: 151554 Hom.: 3843 Cov.: 32 AF XY: 0.188 AC XY: 13940 AN XY: 74038

African (AFR) AF: 0.0440 AC: 1819 AN: 41352

American (AMR) AF: 0.335 AC: 5091 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 651 AN: 3466

East Asian (EAS) AF: 0.692 AC: 3577 AN: 5172

South Asian (SAS) AF: 0.307 AC: 1470 AN: 4796

European-Finnish (FIN) AF: 0.252 AC: 2630 AN: 10452

Middle Eastern (MID) AF: 0.120 AC: 35 AN: 292

European-Non Finnish (NFE) AF: 0.161 AC: 10922 AN: 67786

Other (OTH) AF: 0.190 AC: 400 AN: 2108

Alfa AF: 0.159 Hom.: 299

Bravo AF: 0.179

Asia WGS AF: 0.476 AC: 1649 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28865246, 27821352, 18716611) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Pathogenic	26
DANN	Benign	0.50
PhyloP100		-0.048
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: -1

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

Other links and lift over

dbSNP: rs12134960; hg19: chr1-197009508;