rs4524

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_000130.5(F5):c.2573A>G(p.Lys858Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,613,702 control chromosomes in the GnomAD database, including 60,850 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.25 ( 4802 hom., cov: 32)

Exomes 𝑓: 0.27 ( 56048 hom. )

Consequence

F5
NM_000130.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -0.613

Publications

104 publications found

Variant links:

Genes affected

F5 (HGNC:3542): (coagulation factor V) This gene encodes an essential cofactor of the blood coagulation cascade. This factor circulates in plasma, and is converted to the active form by the release of the activation peptide by thrombin during coagulation. This generates a heavy chain and a light chain which are held together by calcium ions. The activated protein is a cofactor that participates with activated coagulation factor X to activate prothrombin to thrombin. Defects in this gene result in either an autosomal recessive hemorrhagic diathesis or an autosomal dominant form of thrombophilia, which is known as activated protein C resistance. [provided by RefSeq, Oct 2008]

F5 Gene-Disease associations (from GenCC):

thrombophilia due to activated protein C resistance
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
congenital factor V deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
East Texas bleeding disorder
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

F5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.9877167E-4).

BP6

Variant 1-169542517-T-C is Benign according to our data. Variant chr1-169542517-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255200.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000130.5. 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
	F5	NM_000130.5	MANE Select	c.2573A>G	p.Lys858Arg	missense	Exon 13 of 25	NP_000121.2	P12259

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
F5	ENST00000367797.9	TSL:1 MANE Select	c.2573A>G	p.Lys858Arg	missense	Exon 13 of 25	ENSP00000356771.3	P12259
F5	ENST00000367796.3	TSL:5	c.2588A>G	p.Lys863Arg	missense	Exon 13 of 25	ENSP00000356770.3	A0A0A0MRJ7
F5	ENST00000904428.1		c.1611+7284A>G		intron	N/A	ENSP00000574487.1

Frequencies

GnomAD3 genomes

AF:

0.246

AC:

37408

AN:

152014

Hom.:

4790

Cov.:

show subpopulations

Gnomad AFR

AF:

0.183

Gnomad AMI

AF:

0.191

Gnomad AMR

AF:

0.341

Gnomad ASJ

AF:

0.168

Gnomad EAS

AF:

0.234

Gnomad SAS

AF:

0.344

Gnomad FIN

AF:

0.211

Gnomad MID

AF:

0.247

Gnomad NFE

AF:

0.267

Gnomad OTH

AF:

0.263

GnomAD2 exomes

AF:

0.281

AC:

70559

AN:

250882

AF XY:

0.282

show subpopulations

Gnomad AFR exome

AF:

0.179

Gnomad AMR exome

AF:

0.416

Gnomad ASJ exome

AF:

0.177

Gnomad EAS exome

AF:

0.222

Gnomad FIN exome

AF:

0.213

Gnomad NFE exome

AF:

0.268

Gnomad OTH exome

AF:

0.287

GnomAD4 exome

AF:

0.273

AC:

399214

AN:

1461572

Hom.:

56048

Cov.:

AF XY:

0.275

AC XY:

199697

AN XY:

727074

show subpopulations

African (AFR)

AF:

0.180

AC:

6037

AN:

33462

American (AMR)

AF:

0.409

AC:

18276

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.176

AC:

4599

AN:

26130

East Asian (EAS)

AF:

0.226

AC:

8990

AN:

39692

South Asian (SAS)

AF:

0.347

AC:

29906

AN:

86248

European-Finnish (FIN)

AF:

0.217

AC:

11593

AN:

53410

Middle Eastern (MID)

AF:

0.277

AC:

1594

AN:

5764

European-Non Finnish (NFE)

AF:

0.272

AC:

302207

AN:

1111764

Other (OTH)

AF:

0.265

AC:

16012

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

17027

34054

51081

68108

85135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10190

20380

30570

40760

50950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.246

AC:

37448

AN:

152130

Hom.:

4802

Cov.:

AF XY:

0.248

AC XY:

18450

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.183

AC:

7602

AN:

41512

American (AMR)

AF:

0.342

AC:

5222

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

585

AN:

3472

East Asian (EAS)

AF:

0.234

AC:

1210

AN:

5166

South Asian (SAS)

AF:

0.345

AC:

1663

AN:

4822

European-Finnish (FIN)

AF:

0.211

AC:

2239

AN:

10588

Middle Eastern (MID)

AF:

0.238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.267

AC:

18132

AN:

67978

Other (OTH)

AF:

0.261

AC:

551

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1469

2938

4407

5876

7345

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

396

792

1188

1584

1980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.265

Hom.:

26140

Bravo

AF:

0.254

TwinsUK

AF:

0.270

AC:

1000

ALSPAC

AF:

0.281

AC:

1082

ESP6500AA

AF:

0.185

AC:

813

ESP6500EA

AF:

0.274

AC:

2355

ExAC

AF:

0.277

AC:

33595

Asia WGS

AF:

0.289

AC:

1004

AN:

3478

EpiCase

AF:

0.269

EpiControl

AF:

0.270

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Thrombophilia due to activated protein C resistance (2)

Congenital factor V deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.87

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.12

(source)

DANN

Benign

0.12

DEOGEN2

Benign

0.013

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0049

LIST_S2

Benign

0.39

MetaRNN

Benign

0.00050

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-1.4

PhyloP100

-0.61

PrimateAI

Benign

0.19

PROVEAN

Benign

0.21

REVEL

Benign

0.0090

Sift

Benign

0.85

Sift4G

Benign

0.85

Polyphen

0.0

Vest4

0.026

MPC

0.071

ClinPred

0.00071

GERP RS

-1.7

Varity_R

0.022

gMVP

0.13

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over