1-169549874-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000130.5(F5):c.1538G>A(p.Arg513Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0539 in 1,613,922 control chromosomes in the GnomAD database, including 14,717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R513R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.12 ( 2984 hom., cov: 32)

Exomes 𝑓: 0.047 ( 11733 hom. )

Consequence

F5
NM_000130.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.10

Publications

46 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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.3489547E-4).

BP6

Variant 1-169549874-C-T is Benign according to our data. Variant chr1-169549874-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 293628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F5	NM_000130.5 link	c.1538G>A	p.Arg513Lys	missense_variant	Exon 10 of 25	ENST00000367797.9	NP_000121.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F5	ENST00000367797.9 link	c.1538G>A	p.Arg513Lys	missense_variant	Exon 10 of 25	1	NM_000130.5	ENSP00000356771.3
F5	ENST00000367796.3 link	c.1538G>A	p.Arg513Lys	missense_variant	Exon 10 of 25	5		ENSP00000356770.3

Frequencies

GnomAD3 genomes

AF:

0.124

AC:

18830

AN:

152018

Hom.:

2980

Cov.:

show subpopulations

Gnomad AFR

AF:

0.285

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0820

Gnomad ASJ

AF:

0.0689

Gnomad EAS

AF:

0.643

Gnomad SAS

AF:

0.158

Gnomad FIN

AF:

0.0586

Gnomad MID

AF:

0.0541

Gnomad NFE

AF:

0.00920

Gnomad OTH

AF:

0.105

GnomAD2 exomes

AF:

0.111

AC:

27918

AN:

251418

AF XY:

0.103

show subpopulations

Gnomad AFR exome

AF:

0.291

Gnomad AMR exome

AF:

0.113

Gnomad ASJ exome

AF:

0.0610

Gnomad EAS exome

AF:

0.652

Gnomad FIN exome

AF:

0.0545

Gnomad NFE exome

AF:

0.0103

Gnomad OTH exome

AF:

0.0693

GnomAD4 exome

AF:

0.0466

AC:

68142

AN:

1461784

Hom.:

11733

Cov.:

AF XY:

0.0478

AC XY:

34737

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.290

AC:

9691

AN:

33466

American (AMR)

AF:

0.106

AC:

4760

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0568

AC:

1484

AN:

26132

East Asian (EAS)

AF:

0.650

AC:

25805

AN:

39684

South Asian (SAS)

AF:

0.129

AC:

11096

AN:

86246

European-Finnish (FIN)

AF:

0.0521

AC:

2783

AN:

53416

Middle Eastern (MID)

AF:

0.0456

AC:

263

AN:

5768

European-Non Finnish (NFE)

AF:

0.00668

AC:

7433

AN:

1111958

Other (OTH)

AF:

0.0799

AC:

4827

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

2675

5350

8025

10700

13375

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

886

1772

2658

3544

4430

<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:

0.124

AC:

18859

AN:

152138

Hom.:

2984

Cov.:

AF XY:

0.130

AC XY:

9668

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.284

AC:

11796

AN:

41480

American (AMR)

AF:

0.0823

AC:

1258

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0689

AC:

239

AN:

3468

East Asian (EAS)

AF:

0.643

AC:

3315

AN:

5158

South Asian (SAS)

AF:

0.157

AC:

755

AN:

4822

European-Finnish (FIN)

AF:

0.0586

AC:

621

AN:

10592

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00919

AC:

625

AN:

68006

Other (OTH)

AF:

0.111

AC:

235

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

664

1328

1993

2657

3321

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

360

540

720

900

<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:

0.0588

Hom.:

6417

Bravo

AF:

0.136

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.268

AC:

1183

ESP6500EA

AF:

0.0108

AC:

ExAC

AF:

0.112

AC:

13593

Asia WGS

AF:

0.375

AC:

1302

AN:

3478

EpiCase

AF:

0.0108

EpiControl

AF:

0.0104

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32211132, 11950065, 10845571, 9798997, 23662219) -

Congenital factor V deficiency

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Budd-Chiari syndrome

Benign:1

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. -

Factor V deficiency

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Thrombophilia due to activated protein C resistance

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Thrombophilia due to thrombin defect

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

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

0.17

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;T

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.58

T;T

MetaRNN

Benign

0.00073

T;T

MetaSVM

Uncertain

0.74

MutationAssessor

Benign

0.92

L;.

PhyloP100

3.1

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.3

N;N

REVEL

Uncertain

0.44

Sift

Benign

0.25

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.91

P;.

Vest4

0.19

MPC

0.47

ClinPred

0.018

GERP RS

5.7

Varity_R

0.21

gMVP

0.94

Mutation Taster

=91/9

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over