rs6018

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.2450A>C(p.Asn817Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0611 in 1,613,968 control chromosomes in the GnomAD database, including 3,539 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.055 ( 357 hom., cov: 32)

Exomes 𝑓: 0.062 ( 3182 hom. )

Consequence

F5
NM_000130.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.208

Publications

38 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=0.0034109354).

BP6

Variant 1-169542640-T-G is Benign according to our data. Variant chr1-169542640-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F5	NM_000130.5 link	c.2450A>C	p.Asn817Thr	missense_variant	Exon 13 of 25	ENST00000367797.9	NP_000121.2	P12259

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F5	ENST00000367797.9 link	c.2450A>C	p.Asn817Thr	missense_variant	Exon 13 of 25	1	NM_000130.5	ENSP00000356771.3		P12259
F5	ENST00000367796.3 link	c.2465A>C	p.Asn822Thr	missense_variant	Exon 13 of 25	5		ENSP00000356770.3		A0A0A0MRJ7

Frequencies

GnomAD3 genomes

AF:

0.0550

AC:

8356

AN:

152026

Hom.:

356

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0111

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.102

Gnomad ASJ

AF:

0.0750

Gnomad EAS

AF:

0.0299

Gnomad SAS

AF:

0.0730

Gnomad FIN

AF:

0.0839

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0664

Gnomad OTH

AF:

0.0675

GnomAD2 exomes

AF:

0.0654

AC:

16423

AN:

251256

AF XY:

0.0662

show subpopulations

Gnomad AFR exome

AF:

0.00898

Gnomad AMR exome

AF:

0.0957

Gnomad ASJ exome

AF:

0.0699

Gnomad EAS exome

AF:

0.0303

Gnomad FIN exome

AF:

0.0855

Gnomad NFE exome

AF:

0.0628

Gnomad OTH exome

AF:

0.0742

GnomAD4 exome

AF:

0.0618

AC:

90317

AN:

1461824

Hom.:

3182

Cov.:

AF XY:

0.0626

AC XY:

45535

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.00908

AC:

304

AN:

33472

American (AMR)

AF:

0.0962

AC:

4301

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0705

AC:

1843

AN:

26134

East Asian (EAS)

AF:

0.0599

AC:

2380

AN:

39700

South Asian (SAS)

AF:

0.0738

AC:

6365

AN:

86258

European-Finnish (FIN)

AF:

0.0835

AC:

4458

AN:

53420

Middle Eastern (MID)

AF:

0.0893

AC:

515

AN:

5768

European-Non Finnish (NFE)

AF:

0.0597

AC:

66414

AN:

1111964

Other (OTH)

AF:

0.0619

AC:

3737

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

5588

11176

16765

22353

27941

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2416

4832

7248

9664

12080

<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:

0.0549

AC:

8358

AN:

152144

Hom.:

357

Cov.:

AF XY:

0.0573

AC XY:

4260

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0110

AC:

458

AN:

41530

American (AMR)

AF:

0.102

AC:

1560

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0750

AC:

260

AN:

3466

East Asian (EAS)

AF:

0.0300

AC:

155

AN:

5172

South Asian (SAS)

AF:

0.0731

AC:

352

AN:

4816

European-Finnish (FIN)

AF:

0.0839

AC:

889

AN:

10596

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0664

AC:

4515

AN:

67978

Other (OTH)

AF:

0.0673

AC:

142

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

387

774

1160

1547

1934

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

204

306

408

510

<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:

0.0605

Hom.:

1514

Bravo

AF:

0.0514

TwinsUK

AF:

0.0542

AC:

201

ALSPAC

AF:

0.0532

AC:

205

ESP6500AA

AF:

0.00999

AC:

ESP6500EA

AF:

0.0633

AC:

544

ExAC

AF:

0.0617

AC:

7495

Asia WGS

AF:

0.0630

AC:

218

AN:

3478

EpiCase

AF:

0.0628

EpiControl

AF:

0.0635

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

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

- -

Sep 19, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 33103541) -

Thrombophilia due to activated protein C resistance

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Jan 12, 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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Thrombophilia due to thrombin defect

Benign:1

Jan 12, 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

0.18

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.71

CADD

Benign

9.1

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

T;T

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.40

T;T

MetaRNN

Benign

0.0034

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;.

PhyloP100

0.21

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-3.1

D;D

REVEL

Benign

0.017

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.020

D;D

Polyphen

0.068

B;.

Vest4

0.069

MPC

0.11

ClinPred

0.013

GERP RS

2.1

Varity_R

0.079

gMVP

0.24

Mutation Taster

=99/1

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