rs3024477

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr6-6250887-T-A
• chr6-6250887-T-C

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:2
• 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: 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 -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 id 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F13A1	NM_000129.4	c.614A>T	p.Tyr205Phe	missense_variant	Exon 5 of 15	ENST00000264870.8	NP_000120.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F13A1	ENST00000264870.8	c.614A>T	p.Tyr205Phe	missense_variant	Exon 5 of 15	1	NM_000129.4	ENSP00000264870.3
F13A1	ENST00000479211.1	n.*20A>T		downstream_gene_variant		5

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

TwinsUK AF: 0.0318 AC: 118

ALSPAC AF: 0.0267 AC: 103

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.0279 AC: 240

ExAC AF: 0.0172 AC: 2083

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0264

EpiControl AF: 0.0254

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Factor XIII, A subunit, deficiency of Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

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
Vest4		0.26
MPC		0.72
ClinPred		0.025	T
GERP RS		4.7
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

Other links and lift over

dbSNP: rs3024477; hg19: chr6-6251120; COSMIC: COSV99079976; COSMIC: COSV99079976;