rs5985

Variant names:

• chr6-6318562-C-A
• rs5985
• NM_000129.4:c.103G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-6318562-C-A
• chr6-6318562-C-G
• chr6-6318562-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000129.4(F13A1):​c.103G>T​(p.Val35Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,613,256 control chromosomes in the GnomAD database, including 46,576 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.22 (3785 hom., cov: 31)
  • Exomes 𝑓: 0.23 (42791 hom.)
• Consequence: F13A1 NM_000129.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.148
• Publications: 553 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058254898).
• BP6: Variant 6-6318562-C-A is Benign according to our data. Variant chr6-6318562-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 16532.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

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.103G>T	p.Val35Leu	missense	Exon 2 of 15	NP_000120.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F13A1	ENST00000264870.8	TSL:1 MANE Select	c.103G>T	p.Val35Leu	missense	Exon 2 of 15	ENSP00000264870.3
	F13A1	ENST00000950947.1		c.103G>T	p.Val35Leu	missense	Exon 1 of 14	ENSP00000621006.1
	F13A1	ENST00000878383.1		c.103G>T	p.Val35Leu	missense	Exon 2 of 14	ENSP00000548442.1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32635 AN: 151822 Hom.: 3781 Cov.: 31

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.372

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.210

GnomAD2 exomes AF: 0.205 AC: 51336 AN: 250876 AF XY: 0.199

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.255

Gnomad ASJ exome AF: 0.170

Gnomad EAS exome AF: 0.000926

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.253

Gnomad OTH exome AF: 0.212

GnomAD4 exome AF: 0.235 AC: 343358 AN: 1461316 Hom.: 42791 Cov.: 38 AF XY: 0.231 AC XY: 168144 AN XY: 726956

African (AFR) AF: 0.180 AC: 6006 AN: 33454

American (AMR) AF: 0.254 AC: 11322 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 4447 AN: 26114

East Asian (EAS) AF: 0.000756 AC: 30 AN: 39700

South Asian (SAS) AF: 0.116 AC: 10033 AN: 86164

European-Finnish (FIN) AF: 0.207 AC: 11042 AN: 53374

Middle Eastern (MID) AF: 0.134 AC: 767 AN: 5742

European-Non Finnish (NFE) AF: 0.258 AC: 286914 AN: 1111764

Other (OTH) AF: 0.212 AC: 12797 AN: 60354

GnomAD4 genome AF: 0.215 AC: 32673 AN: 151940 Hom.: 3785 Cov.: 31 AF XY: 0.210 AC XY: 15580 AN XY: 74258

African (AFR) AF: 0.184 AC: 7643 AN: 41444

American (AMR) AF: 0.230 AC: 3516 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 588 AN: 3466

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5178

South Asian (SAS) AF: 0.117 AC: 561 AN: 4806

European-Finnish (FIN) AF: 0.206 AC: 2169 AN: 10532

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17369 AN: 67920

Other (OTH) AF: 0.207 AC: 439 AN: 2116

Alfa AF: 0.235 Hom.: 20362

Bravo AF: 0.217

TwinsUK AF: 0.256 AC: 950

ALSPAC AF: 0.241 AC: 929

ESP6500AA AF: 0.182 AC: 804

ESP6500EA AF: 0.252 AC: 2163

ExAC AF: 0.206 AC: 24994

Asia WGS AF: 0.0640 AC: 225 AN: 3478

EpiCase AF: 0.240

EpiControl AF: 0.236

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Factor XIII, A subunit, deficiency of (1)
-	-	1	Myocardial infarction, protection against (2)
-	-	1	not specified (1)
-	-	-	Venous thrombosis, protection against (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.015
DANN	Benign	0.36
DEOGEN2	Benign	0.0065	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.15
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.22
Sift	Benign	1.0	T
Sift4G	Benign	0.43	T
Vest4		0.018
MutPred		0.52		Loss of sheet (P = 0.0817)
MPC		0.22
ClinPred		0.00055	T
GERP RS		1.9
gMVP		0.25
Mutation Taster		=98/2	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: rs5985; hg19: chr6-6318795; COSMIC: COSV53558584;