rs3024480

Variant names:

• chr6-6222016-T-C
• rs3024480
• NM_000129.4:c.1112+17A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000129.4(F13A1):​c.1112+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00827 in 1,612,940 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (33 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (81 hom.)
• Consequence: F13A1 NM_000129.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.549
• Publications: 2 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-6222016-T-C is Benign according to our data. Variant chr6-6222016-T-C is described in ClinVar as Benign. ClinVar VariationId is 255182.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0133 (2023/152308) while in subpopulation AFR AF = 0.0262 (1089/41558). AF 95% confidence interval is 0.0249. There are 33 homozygotes in GnomAd4. There are 966 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000129.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F13A1	NM_000129.4	MANE Select	c.1112+17A>G		intron	N/A	NP_000120.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F13A1	ENST00000264870.8	TSL:1 MANE Select	c.1112+17A>G		intron	N/A	ENSP00000264870.3
	F13A1	ENST00000950947.1		c.1112+17A>G		intron	N/A	ENSP00000621006.1
	F13A1	ENST00000878383.1		c.923+17A>G		intron	N/A	ENSP00000548442.1

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2009 AN: 152190 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00858

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.00892 AC: 2233 AN: 250316 AF XY: 0.00901

Gnomad AFR exome AF: 0.0265

Gnomad AMR exome AF: 0.00750

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000993

Gnomad NFE exome AF: 0.00867

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.00774 AC: 11308 AN: 1460632 Hom.: 81 Cov.: 31 AF XY: 0.00790 AC XY: 5744 AN XY: 726684

African (AFR) AF: 0.0252 AC: 842 AN: 33464

American (AMR) AF: 0.00807 AC: 361 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 528 AN: 26128

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39678

South Asian (SAS) AF: 0.00835 AC: 720 AN: 86232

European-Finnish (FIN) AF: 0.00134 AC: 71 AN: 52874

Middle Eastern (MID) AF: 0.0516 AC: 297 AN: 5758

European-Non Finnish (NFE) AF: 0.00702 AC: 7797 AN: 1111434

Other (OTH) AF: 0.0114 AC: 689 AN: 60354

GnomAD4 genome AF: 0.0133 AC: 2023 AN: 152308 Hom.: 33 Cov.: 32 AF XY: 0.0130 AC XY: 966 AN XY: 74484

African (AFR) AF: 0.0262 AC: 1089 AN: 41558

American (AMR) AF: 0.0111 AC: 170 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00725 AC: 35 AN: 4826

European-Finnish (FIN) AF: 0.000941 AC: 10 AN: 10622

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.00859 AC: 584 AN: 68022

Other (OTH) AF: 0.0161 AC: 34 AN: 2110

Alfa AF: 0.0131 Hom.: 4

Bravo AF: 0.0140

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.4
DANN	Benign	0.62
PhyloP100		0.55
Mutation Taster		=100/0	polymorphism

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: rs3024480; hg19: chr6-6222249;