1-169529737-T-C

Variant names:

Variant summary

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

The NM_000130.5(F5):c.5290A>G(p.Met1764Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,613,296 control chromosomes in the GnomAD database, including 89,570 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.30 ( 7249 hom., cov: 32)

Exomes 𝑓: 0.33 ( 82321 hom. )

Consequence

F5
NM_000130.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.27

Publications

65 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=1.3938546E-4).

BP6

Variant 1-169529737-T-C is Benign according to our data. Variant chr1-169529737-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255210.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.433 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.5290A>G	p.Met1764Val	missense	Exon 16 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.5290A>G	p.Met1764Val	missense	Exon 16 of 25	ENSP00000356771.3	P12259
F5	ENST00000367796.3	TSL:5	c.5305A>G	p.Met1769Val	missense	Exon 16 of 25	ENSP00000356770.3	A0A0A0MRJ7
F5	ENST00000904428.1		c.1930A>G	p.Met644Val	missense	Exon 12 of 21	ENSP00000574487.1

Frequencies

GnomAD3 genomes

AF:

0.299

AC:

45508

AN:

151956

Hom.:

7240

Cov.:

show subpopulations

Gnomad AFR

AF:

0.197

Gnomad AMI

AF:

0.192

Gnomad AMR

AF:

0.440

Gnomad ASJ

AF:

0.241

Gnomad EAS

AF:

0.270

Gnomad SAS

AF:

0.400

Gnomad FIN

AF:

0.290

Gnomad MID

AF:

0.323

Gnomad NFE

AF:

0.330

Gnomad OTH

AF:

0.330

GnomAD2 exomes

AF:

0.343

AC:

86072

AN:

250926

AF XY:

0.344

show subpopulations

Gnomad AFR exome

AF:

0.192

Gnomad AMR exome

AF:

0.510

Gnomad ASJ exome

AF:

0.245

Gnomad EAS exome

AF:

0.258

Gnomad FIN exome

AF:

0.294

Gnomad NFE exome

AF:

0.328

Gnomad OTH exome

AF:

0.353

GnomAD4 exome

AF:

0.332

AC:

485070

AN:

1461222

Hom.:

82321

Cov.:

AF XY:

0.334

AC XY:

242557

AN XY:

726920

show subpopulations

African (AFR)

AF:

0.191

AC:

6379

AN:

33438

American (AMR)

AF:

0.504

AC:

22510

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.243

AC:

6355

AN:

26116

East Asian (EAS)

AF:

0.297

AC:

11801

AN:

39680

South Asian (SAS)

AF:

0.402

AC:

34628

AN:

86238

European-Finnish (FIN)

AF:

0.296

AC:

15810

AN:

53390

Middle Eastern (MID)

AF:

0.343

AC:

1978

AN:

5764

European-Non Finnish (NFE)

AF:

0.329

AC:

366187

AN:

1111530

Other (OTH)

AF:

0.322

AC:

19422

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

17507

35014

52520

70027

87534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11876

23752

35628

47504

59380

<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:

0.299

AC:

45534

AN:

152074

Hom.:

7249

Cov.:

AF XY:

0.304

AC XY:

22571

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.196

AC:

8147

AN:

41514

American (AMR)

AF:

0.441

AC:

6729

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.241

AC:

838

AN:

3472

East Asian (EAS)

AF:

0.270

AC:

1399

AN:

5178

South Asian (SAS)

AF:

0.401

AC:

1931

AN:

4820

European-Finnish (FIN)

AF:

0.290

AC:

3069

AN:

10572

Middle Eastern (MID)

AF:

0.313

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.331

AC:

22463

AN:

67956

Other (OTH)

AF:

0.327

AC:

691

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1609

3218

4827

6436

8045

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

466

932

1398

1864

2330

<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:

0.324

Hom.:

38495

Bravo

AF:

0.305

TwinsUK

AF:

0.322

AC:

1193

ALSPAC

AF:

0.333

AC:

1285

ESP6500AA

AF:

0.199

AC:

878

ESP6500EA

AF:

0.336

AC:

2886

ExAC

AF:

0.335

AC:

40667

Asia WGS

AF:

0.344

AC:

1195

AN:

3478

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

0.051

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.012

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.012

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.032

MetaRNN

Benign

0.00014

MetaSVM

Benign

-0.43

MutationAssessor

Benign

-1.2

PhyloP100

-2.3

PrimateAI

Benign

0.20

PROVEAN

Benign

0.77

REVEL

Benign

0.23

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.0060

MPC

0.087

ClinPred

0.0039

GERP RS

-2.9

Varity_R

0.11

gMVP

0.58

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over