6-6250887-T-A

Variant names:

• chr6-6250887-T-A
• rs3024477
• NM_000129.4:c.614A>T
• F13A1 p.Tyr205Phe

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000129.4(F13A1):​c.614A>T​(p.Tyr205Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0249 in 1,613,014 control chromosomes in the GnomAD database, including 609 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (40 hom., cov: 33)
  • Exomes 𝑓: 0.026 (569 hom.)
• Consequence: F13A1 NM_000129.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.44
• Publications: 29 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: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• congenital factor XIII deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.010353804).
• BP6: Variant 6-6250887-T-A is Benign according to our data. Variant chr6-6250887-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 908780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0186 (2840/152300) while in subpopulation NFE AF = 0.0292 (1985/68018). AF 95% confidence interval is 0.0281. There are 40 homozygotes in GnomAd4. There are 1373 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F13A1	NM_000129.4	MANE Select	c.614A>T	p.Tyr205Phe	missense	Exon 5 of 15	NP_000120.2	P00488

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F13A1	ENST00000264870.8	TSL:1 MANE Select	c.614A>T	p.Tyr205Phe	missense	Exon 5 of 15	ENSP00000264870.3	P00488
	F13A1	ENST00000950947.1		c.614A>T	p.Tyr205Phe	missense	Exon 4 of 14	ENSP00000621006.1
	F13A1	ENST00000878383.1		c.425A>T	p.Tyr142Phe	missense	Exon 4 of 14	ENSP00000548442.1

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2841 AN: 152182 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.00540

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.00668

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0364

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0292

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.0179 AC: 4499 AN: 251072 AF XY: 0.0176

Gnomad AFR exome AF: 0.00461

Gnomad AMR exome AF: 0.00613

Gnomad ASJ exome AF: 0.0208

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0352

Gnomad NFE exome AF: 0.0269

Gnomad OTH exome AF: 0.0162

GnomAD4 exome AF: 0.0256 AC: 37325 AN: 1460714 Hom.: 569 Cov.: 31 AF XY: 0.0248 AC XY: 18015 AN XY: 726714

African (AFR) AF: 0.00376 AC: 126 AN: 33470

American (AMR) AF: 0.00704 AC: 315 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0203 AC: 530 AN: 26126

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39676

South Asian (SAS) AF: 0.00325 AC: 280 AN: 86244

European-Finnish (FIN) AF: 0.0356 AC: 1891 AN: 53184

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5764

European-Non Finnish (NFE) AF: 0.0296 AC: 32842 AN: 1111166

Other (OTH) AF: 0.0219 AC: 1320 AN: 60368

GnomAD4 genome AF: 0.0186 AC: 2840 AN: 152300 Hom.: 40 Cov.: 33 AF XY: 0.0184 AC XY: 1373 AN XY: 74480

African (AFR) AF: 0.00539 AC: 224 AN: 41572

American (AMR) AF: 0.00660 AC: 101 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4828

European-Finnish (FIN) AF: 0.0364 AC: 386 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0292 AC: 1985 AN: 68018

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.0239 Hom.: 54

Bravo AF: 0.0161

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0264

EpiControl AF: 0.0254

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Factor XIII, A subunit, deficiency of (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	0.98
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.92	D
MetaRNN	Benign	0.010	T
MetaSVM	Pathogenic	0.81	D
PhyloP100		3.4
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.58
Sift	Benign	0.056	T
Sift4G	Benign	0.21	T
gMVP		0.34
Mutation Taster		=87/13	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3024477;

hg19: chr6-6251120;

COSMIC: COSV99079976;

COSMIC: COSV99079976;