NM_000129.4:c.-19+12A>C

Variant names:

• chr6-6320575-T-G
• rs2815822
• NM_000129.4:c.-19+12A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000129.4(F13A1):​c.-19+12A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 466,414 control chromosomes in the GnomAD database, including 177,234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (59146 hom., cov: 33)
  • Exomes 𝑓: 0.87 (118088 hom.)
• Consequence: F13A1 NM_000129.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.36
• Publications: 13 publications found

Genes affected

F13A1 (HGNC:3531): (coagulation factor XIII A chain) This gene encodes the coagulation factor XIII A 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 plasma carrier molecules. Platelet factor XIII is comprised only of 2 A subunits, which are identical to those of plasma origin. Upon 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. It also crosslinks alpha-2-plasmin inhibitor, or fibronectin, to the alpha chains of fibrin. 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]

F13A1 Gene-Disease associations (from GenCC):

• factor XIII, A subunit, deficiency of

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• congenital factor XIII deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000309672 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-6320575-T-G is Benign according to our data. Variant chr6-6320575-T-G is described in ClinVar as Benign. ClinVar VariationId is 357680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.933 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F13A1	NM_000129.4	c.-19+12A>C		intron_variant	Intron 1 of 14	ENST00000264870.8	NP_000120.2
LOC124901253	XR_007059428.1	n.55-9178T>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F13A1	ENST00000264870.8	c.-19+12A>C		intron_variant	Intron 1 of 14	1	NM_000129.4	ENSP00000264870.3

Frequencies

GnomAD3 genomes AF: 0.881 AC: 134043 AN: 152090 Hom.: 59096 Cov.: 33

Gnomad AFR AF: 0.890

Gnomad AMI AF: 0.863

Gnomad AMR AF: 0.866

Gnomad ASJ AF: 0.855

Gnomad EAS AF: 0.956

Gnomad SAS AF: 0.795

Gnomad FIN AF: 0.854

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.887

Gnomad OTH AF: 0.872

GnomAD2 exomes AF: 0.870 AC: 125895 AN: 144754 AF XY: 0.866

Gnomad AFR exome AF: 0.892

Gnomad AMR exome AF: 0.857

Gnomad ASJ exome AF: 0.858

Gnomad EAS exome AF: 0.954

Gnomad FIN exome AF: 0.860

Gnomad NFE exome AF: 0.894

Gnomad OTH exome AF: 0.860

GnomAD4 exome AF: 0.866 AC: 271953 AN: 314206 Hom.: 118088 Cov.: 0 AF XY: 0.859 AC XY: 152366 AN XY: 177384

African (AFR) AF: 0.889 AC: 7590 AN: 8534

American (AMR) AF: 0.857 AC: 22979 AN: 26808

Ashkenazi Jewish (ASJ) AF: 0.854 AC: 8929 AN: 10458

East Asian (EAS) AF: 0.956 AC: 8783 AN: 9186

South Asian (SAS) AF: 0.792 AC: 46743 AN: 59002

European-Finnish (FIN) AF: 0.862 AC: 23157 AN: 26876

Middle Eastern (MID) AF: 0.819 AC: 2258 AN: 2756

European-Non Finnish (NFE) AF: 0.890 AC: 139242 AN: 156486

Other (OTH) AF: 0.870 AC: 12272 AN: 14100

GnomAD4 genome AF: 0.881 AC: 134148 AN: 152208 Hom.: 59146 Cov.: 33 AF XY: 0.879 AC XY: 65428 AN XY: 74418

African (AFR) AF: 0.890 AC: 36955 AN: 41528

American (AMR) AF: 0.866 AC: 13245 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.855 AC: 2968 AN: 3472

East Asian (EAS) AF: 0.956 AC: 4921 AN: 5150

South Asian (SAS) AF: 0.795 AC: 3832 AN: 4818

European-Finnish (FIN) AF: 0.854 AC: 9070 AN: 10620

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.887 AC: 60299 AN: 68004

Other (OTH) AF: 0.869 AC: 1838 AN: 2114

Alfa AF: 0.883 Hom.: 98483

Bravo AF: 0.887

Asia WGS AF: 0.838 AC: 2915 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

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

- -

Factor XIII, A subunit, deficiency of Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

not provided Benign:1

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21512576, 23508224) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.34
PhyloP100		-3.4
PromoterAI		-0.13	Neutral
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: rs2815822; hg19: chr6-6320808;