1-169541237-G-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.3853C>A(p.Leu1285Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,603,754 control chromosomes in the GnomAD database, including 24,165 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 1350 hom., cov: 26)

Exomes 𝑓: 0.17 ( 22815 hom. )

Consequence

F5
NM_000130.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:9

Conservation

PhyloP100: -0.143

Publications

22 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=0.0068129003).

BP6

Variant 1-169541237-G-T is Benign according to our data. Variant chr1-169541237-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F5	NM_000130.5 link	c.3853C>A	p.Leu1285Ile	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.3853C>A	p.Leu1285Ile	missense_variant	Exon 13 of 25	1	NM_000130.5	ENSP00000356771.3		P12259
F5	ENST00000367796.3 link	c.3868C>A	p.Leu1290Ile	missense_variant	Exon 13 of 25	5		ENSP00000356770.3		A0A0A0MRJ7

Frequencies

GnomAD3 genomes

AF:

0.162

AC:

23833

AN:

147284

Hom.:

1353

Cov.:

show subpopulations

Gnomad AFR

AF:

0.157

Gnomad AMI

AF:

0.122

Gnomad AMR

AF:

0.145

Gnomad ASJ

AF:

0.225

Gnomad EAS

AF:

0.0917

Gnomad SAS

AF:

0.184

Gnomad FIN

AF:

0.192

Gnomad MID

AF:

0.172

Gnomad NFE

AF:

0.165

Gnomad OTH

AF:

0.163

GnomAD2 exomes

AF:

0.174

AC:

43421

AN:

249792

AF XY:

0.177

show subpopulations

Gnomad AFR exome

AF:

0.169

Gnomad AMR exome

AF:

0.132

Gnomad ASJ exome

AF:

0.252

Gnomad EAS exome

AF:

0.0957

Gnomad FIN exome

AF:

0.204

Gnomad NFE exome

AF:

0.180

Gnomad OTH exome

AF:

0.172

GnomAD4 exome

AF:

0.174

AC:

253871

AN:

1456364

Hom.:

22815

Cov.:

129

AF XY:

0.175

AC XY:

127054

AN XY:

724344

show subpopulations

African (AFR)

AF:

0.173

AC:

5766

AN:

33290

American (AMR)

AF:

0.137

AC:

6054

AN:

44048

Ashkenazi Jewish (ASJ)

AF:

0.251

AC:

6534

AN:

25990

East Asian (EAS)

AF:

0.0892

AC:

3526

AN:

39548

South Asian (SAS)

AF:

0.199

AC:

16933

AN:

85180

European-Finnish (FIN)

AF:

0.204

AC:

10854

AN:

53170

Middle Eastern (MID)

AF:

0.158

AC:

910

AN:

5748

European-Non Finnish (NFE)

AF:

0.174

AC:

192715

AN:

1109260

Other (OTH)

AF:

0.176

AC:

10579

AN:

60130

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

13787

27573

41360

55146

68933

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6764

13528

20292

27056

33820

<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:

0.162

AC:

23841

AN:

147390

Hom.:

1350

Cov.:

AF XY:

0.162

AC XY:

11665

AN XY:

71960

show subpopulations

African (AFR)

AF:

0.157

AC:

6245

AN:

39850

American (AMR)

AF:

0.145

AC:

2158

AN:

14900

Ashkenazi Jewish (ASJ)

AF:

0.225

AC:

761

AN:

3380

East Asian (EAS)

AF:

0.0915

AC:

459

AN:

5018

South Asian (SAS)

AF:

0.184

AC:

843

AN:

4572

European-Finnish (FIN)

AF:

0.192

AC:

1923

AN:

10010

Middle Eastern (MID)

AF:

0.180

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.165

AC:

10959

AN:

66426

Other (OTH)

AF:

0.162

AC:

333

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

913

1826

2738

3651

4564

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

270

540

810

1080

1350

<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:

0.179

Hom.:

2127

TwinsUK

AF:

0.183

AC:

677

ALSPAC

AF:

0.173

AC:

667

ESP6500AA

AF:

0.176

AC:

775

ESP6500EA

AF:

0.175

AC:

1502

ExAC

AF:

0.179

AC:

21699

Asia WGS

AF:

0.154

AC:

535

AN:

3462

EpiCase

AF:

0.183

EpiControl

AF:

0.183

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 25.185% in gnomAD_ExomesFounderPop) based on the frequency threshold of 5.0% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease. -

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

0.097

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.20

(source)

DANN

Benign

0.16

DEOGEN2

Benign

0.028

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.099

LIST_S2

Benign

0.55

T;T

MetaRNN

Benign

0.0068

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

-0.14

PrimateAI

Benign

0.17

PROVEAN

Benign

-0.29

N;N

REVEL

Benign

0.031

Sift

Benign

0.15

T;T

Sift4G

Benign

0.29

T;T

Polyphen

0.0030

B;.

Vest4

0.083

MPC

0.22

ClinPred

0.0053

GERP RS

-1.4

Varity_R

0.024

gMVP

0.19

Mutation Taster

=97/3

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