rs5982

Variant names:

• chr6-6174633-G-A
• rs5982
• NM_000129.4:c.1694C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-6174633-G-A
• chr6-6174633-G-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.1694C>T​(p.Pro565Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 1,613,906 control chromosomes in the GnomAD database, including 38,795 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). Synonymous variant affecting the same amino acid position (i.e. P565P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.20 (3094 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35701 hom.)
• Consequence: F13A1 NM_000129.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.58
• Publications: 46 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069898665).
• BP6: Variant 6-6174633-G-A is Benign according to our data. Variant chr6-6174633-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255183.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F13A1	NM_000129.4	c.1694C>T	p.Pro565Leu	missense_variant	Exon 12 of 15	ENST00000264870.8	NP_000120.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F13A1	ENST00000264870.8	c.1694C>T	p.Pro565Leu	missense_variant	Exon 12 of 15	1	NM_000129.4	ENSP00000264870.3

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29762 AN: 151976 Hom.: 3090 Cov.: 32

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.196

GnomAD2 exomes AF: 0.212 AC: 53317 AN: 251446 AF XY: 0.223

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.0951

Gnomad ASJ exome AF: 0.224

Gnomad EAS exome AF: 0.321

Gnomad FIN exome AF: 0.207

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.207

GnomAD4 exome AF: 0.216 AC: 315131 AN: 1461812 Hom.: 35701 Cov.: 40 AF XY: 0.219 AC XY: 159585 AN XY: 727206

African (AFR) AF: 0.154 AC: 5152 AN: 33480

American (AMR) AF: 0.101 AC: 4530 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 5776 AN: 26134

East Asian (EAS) AF: 0.302 AC: 11970 AN: 39700

South Asian (SAS) AF: 0.328 AC: 28282 AN: 86258

European-Finnish (FIN) AF: 0.203 AC: 10851 AN: 53420

Middle Eastern (MID) AF: 0.253 AC: 1456 AN: 5766

European-Non Finnish (NFE) AF: 0.210 AC: 233539 AN: 1111942

Other (OTH) AF: 0.225 AC: 13575 AN: 60388

GnomAD4 genome AF: 0.196 AC: 29785 AN: 152094 Hom.: 3094 Cov.: 32 AF XY: 0.199 AC XY: 14758 AN XY: 74342

African (AFR) AF: 0.159 AC: 6586 AN: 41514

American (AMR) AF: 0.135 AC: 2069 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 760 AN: 3470

East Asian (EAS) AF: 0.306 AC: 1579 AN: 5152

South Asian (SAS) AF: 0.348 AC: 1674 AN: 4812

European-Finnish (FIN) AF: 0.213 AC: 2252 AN: 10560

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.209 AC: 14187 AN: 67982

Other (OTH) AF: 0.196 AC: 414 AN: 2116

Alfa AF: 0.203 Hom.: 7021

Bravo AF: 0.182

TwinsUK AF: 0.210 AC: 777

ALSPAC AF: 0.198 AC: 765

ESP6500AA AF: 0.158 AC: 697

ESP6500EA AF: 0.210 AC: 1807

ExAC AF: 0.216 AC: 26217

Asia WGS AF: 0.281 AC: 978 AN: 3478

EpiCase AF: 0.212

EpiControl AF: 0.213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 9920838, 11108652, 20384622) -

Oct 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

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

- -

Mar 06, 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 specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	20
DANN	Benign	0.38
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.45	N
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.6
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.077
Sift	Benign	0.73	T
Sift4G	Benign	0.67	T
Vest4		0.036
MPC		0.23
ClinPred		0.012	T
GERP RS		5.8
gMVP		0.58
Mutation Taster		=90/10	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: rs5982; hg19: chr6-6174866; COSMIC: COSV53555780;