rs13306334

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.4189C>T(p.Leu1397Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,612,520 control chromosomes in the GnomAD database, including 10,768 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 1209 hom., cov: 32)

Exomes 𝑓: 0.039 ( 9559 hom. )

Consequence

F5
NM_000130.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.417

Publications

21 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=5.7811585E-6).

BP6

Variant 1-169540901-G-A is Benign according to our data. Variant chr1-169540901-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 293600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F5	NM_000130.5 link	c.4189C>T	p.Leu1397Phe	missense_variant	Exon 13 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.4189C>T	p.Leu1397Phe	missense_variant	Exon 13 of 25	1	NM_000130.5	ENSP00000356771.3
F5	ENST00000367796.3 link	c.4204C>T	p.Leu1402Phe	missense_variant	Exon 13 of 25	5		ENSP00000356770.3

Frequencies

GnomAD3 genomes

AF:

0.0466

AC:

7078

AN:

152036

Hom.:

1204

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00606

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0749

Gnomad ASJ

AF:

0.0323

Gnomad EAS

AF:

0.627

Gnomad SAS

AF:

0.161

Gnomad FIN

AF:

0.0819

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00884

Gnomad OTH

AF:

0.0450

GnomAD2 exomes

AF:

0.0955

AC:

23952

AN:

250932

AF XY:

0.0922

show subpopulations

Gnomad AFR exome

AF:

0.00548

Gnomad AMR exome

AF:

0.126

Gnomad ASJ exome

AF:

0.0283

Gnomad EAS exome

AF:

0.646

Gnomad FIN exome

AF:

0.0779

Gnomad NFE exome

AF:

0.00977

Gnomad OTH exome

AF:

0.0630

GnomAD4 exome

AF:

0.0389

AC:

56798

AN:

1460366

Hom.:

9559

Cov.:

AF XY:

0.0414

AC XY:

30043

AN XY:

726526

show subpopulations

African (AFR)

AF:

0.00386

AC:

129

AN:

33440

American (AMR)

AF:

0.117

AC:

5167

AN:

44322

Ashkenazi Jewish (ASJ)

AF:

0.0273

AC:

712

AN:

26084

East Asian (EAS)

AF:

0.613

AC:

24319

AN:

39654

South Asian (SAS)

AF:

0.135

AC:

11661

AN:

86138

European-Finnish (FIN)

AF:

0.0763

AC:

4077

AN:

53406

Middle Eastern (MID)

AF:

0.0227

AC:

131

AN:

5762

European-Non Finnish (NFE)

AF:

0.00626

AC:

6958

AN:

1111228

Other (OTH)

AF:

0.0604

AC:

3644

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

3244

6489

9733

12978

16222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

688

1376

2064

2752

3440

<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:

0.0466

AC:

7087

AN:

152154

Hom.:

1209

Cov.:

AF XY:

0.0555

AC XY:

4129

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.00604

AC:

251

AN:

41554

American (AMR)

AF:

0.0753

AC:

1150

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0323

AC:

112

AN:

3466

East Asian (EAS)

AF:

0.626

AC:

3218

AN:

5140

South Asian (SAS)

AF:

0.161

AC:

772

AN:

4804

European-Finnish (FIN)

AF:

0.0819

AC:

868

AN:

10596

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00884

AC:

601

AN:

68006

Other (OTH)

AF:

0.0521

AC:

110

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

228

455

683

910

1138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

264

352

440

<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:

0.0343

Hom.:

3641

Bravo

AF:

0.0465

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.00814

AC:

ExAC

AF:

0.0898

AC:

10902

Asia WGS

AF:

0.356

AC:

1234

AN:

3478

EpiCase

AF:

0.00878

EpiControl

AF:

0.00759

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

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

- -

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

- -

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

0.094

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.77

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.034

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.37

T;T

MetaRNN

Benign

0.0000058

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;.

PhyloP100

-0.42

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.35

N;N

REVEL

Benign

0.033

Sift

Benign

0.26

T;T

Sift4G

Benign

0.72

T;T

Polyphen

0.012

B;.

Vest4

0.086

MPC

0.093

ClinPred

0.0016

GERP RS

1.3

Varity_R

0.029

gMVP

0.25

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