NM_000130.5:c.2208C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000130.5(F5):c.2208C>T(p.Ile736Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,613,338 control chromosomes in the GnomAD database, including 60,137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 4756 hom., cov: 32)

Exomes 𝑓: 0.27 ( 55381 hom. )

Consequence

F5
NM_000130.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.212

Publications

25 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 1-169542882-G-A is Benign according to our data. Variant chr1-169542882-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.212 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F5	NM_000130.5 link	c.2208C>T	p.Ile736Ile	synonymous_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.2208C>T	p.Ile736Ile	synonymous_variant	Exon 13 of 25	1	NM_000130.5	ENSP00000356771.3
F5	ENST00000367796.3 link	c.2223C>T	p.Ile741Ile	synonymous_variant	Exon 13 of 25	5		ENSP00000356770.3

Frequencies

GnomAD3 genomes

AF:

0.245

AC:

37284

AN:

152002

Hom.:

4744

Cov.:

show subpopulations

Gnomad AFR

AF:

0.183

Gnomad AMI

AF:

0.192

Gnomad AMR

AF:

0.341

Gnomad ASJ

AF:

0.168

Gnomad EAS

AF:

0.235

Gnomad SAS

AF:

0.323

Gnomad FIN

AF:

0.211

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.267

Gnomad OTH

AF:

0.262

GnomAD2 exomes

AF:

0.278

AC:

69914

AN:

251090

AF XY:

0.278

show subpopulations

Gnomad AFR exome

AF:

0.178

Gnomad AMR exome

AF:

0.415

Gnomad ASJ exome

AF:

0.177

Gnomad EAS exome

AF:

0.222

Gnomad FIN exome

AF:

0.213

Gnomad NFE exome

AF:

0.268

Gnomad OTH exome

AF:

0.285

GnomAD4 exome

AF:

0.272

AC:

397076

AN:

1461218

Hom.:

55381

Cov.:

AF XY:

0.273

AC XY:

198201

AN XY:

726928

show subpopulations

African (AFR)

AF:

0.180

AC:

6023

AN:

33464

American (AMR)

AF:

0.409

AC:

18274

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.176

AC:

4598

AN:

26130

East Asian (EAS)

AF:

0.226

AC:

8983

AN:

39696

South Asian (SAS)

AF:

0.325

AC:

28066

AN:

86246

European-Finnish (FIN)

AF:

0.217

AC:

11592

AN:

53412

Middle Eastern (MID)

AF:

0.275

AC:

1589

AN:

5768

European-Non Finnish (NFE)

AF:

0.272

AC:

302002

AN:

1111406

Other (OTH)

AF:

0.264

AC:

15949

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

16247

32494

48740

64987

81234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10168

20336

30504

40672

50840

<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:

0.245

AC:

37325

AN:

152120

Hom.:

4756

Cov.:

AF XY:

0.247

AC XY:

18365

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.183

AC:

7595

AN:

41516

American (AMR)

AF:

0.342

AC:

5221

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

583

AN:

3468

East Asian (EAS)

AF:

0.235

AC:

1218

AN:

5186

South Asian (SAS)

AF:

0.324

AC:

1560

AN:

4820

European-Finnish (FIN)

AF:

0.211

AC:

2230

AN:

10576

Middle Eastern (MID)

AF:

0.231

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.267

AC:

18127

AN:

67976

Other (OTH)

AF:

0.260

AC:

549

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1427

2855

4282

5710

7137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

394

788

1182

1576

1970

<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:

0.263

Hom.:

16753

Bravo

AF:

0.254

Asia WGS

AF:

0.283

AC:

983

AN:

3478

EpiCase

AF:

0.269

EpiControl

AF:

0.270

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign: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

- -

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

BayesDel_noAF

Benign

-0.71

CADD

Benign

1.4

(source)

DANN

Benign

0.63

PhyloP100

0.21

Mutation Taster

=100/0

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