rs9332607

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.4095C>T(p.Thr1365Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 1,609,928 control chromosomes in the GnomAD database, including 119,203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 6316 hom., cov: 31)

Exomes 𝑓: 0.38 ( 112887 hom. )

Consequence

F5
NM_000130.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.62

Publications

7 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=-0.87).

BP6

Variant 1-169540995-G-A is Benign according to our data. Variant chr1-169540995-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.62 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F5	NM_000130.5 link	c.4095C>T	p.Thr1365Thr	synonymous_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.4095C>T	p.Thr1365Thr	synonymous_variant	Exon 13 of 25	1	NM_000130.5	ENSP00000356771.3		P12259
F5	ENST00000367796.3 link	c.4110C>T	p.Thr1370Thr	synonymous_variant	Exon 13 of 25	5		ENSP00000356770.3		A0A0A0MRJ7

Frequencies

GnomAD3 genomes

AF:

0.289

AC:

42938

AN:

148770

Hom.:

6316

Cov.:

show subpopulations

Gnomad AFR

AF:

0.175

Gnomad AMI

AF:

0.509

Gnomad AMR

AF:

0.236

Gnomad ASJ

AF:

0.328

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.164

Gnomad FIN

AF:

0.343

Gnomad MID

AF:

0.274

Gnomad NFE

AF:

0.389

Gnomad OTH

AF:

0.300

GnomAD2 exomes

AF:

0.294

AC:

73699

AN:

250494

AF XY:

0.299

show subpopulations

Gnomad AFR exome

AF:

0.182

Gnomad AMR exome

AF:

0.172

Gnomad ASJ exome

AF:

0.345

Gnomad EAS exome

AF:

0.000544

Gnomad FIN exome

AF:

0.368

Gnomad NFE exome

AF:

0.405

Gnomad OTH exome

AF:

0.325

GnomAD4 exome

AF:

0.379

AC:

553539

AN:

1461038

Hom.:

112887

Cov.:

107

AF XY:

0.374

AC XY:

271948

AN XY:

726818

show subpopulations

African (AFR)

AF:

0.181

AC:

6061

AN:

33458

American (AMR)

AF:

0.182

AC:

8108

AN:

44562

Ashkenazi Jewish (ASJ)

AF:

0.350

AC:

9130

AN:

26104

East Asian (EAS)

AF:

0.000605

AC:

AN:

39678

South Asian (SAS)

AF:

0.187

AC:

16146

AN:

86170

European-Finnish (FIN)

AF:

0.366

AC:

19540

AN:

53412

Middle Eastern (MID)

AF:

0.304

AC:

1755

AN:

5764

European-Non Finnish (NFE)

AF:

0.425

AC:

471863

AN:

1111548

Other (OTH)

AF:

0.347

AC:

20912

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

27030

54059

81089

108118

135148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14118

28236

42354

56472

70590

<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:

0.288

AC:

42938

AN:

148890

Hom.:

6316

Cov.:

AF XY:

0.281

AC XY:

20454

AN XY:

72864

show subpopulations

African (AFR)

AF:

0.175

AC:

7177

AN:

41038

American (AMR)

AF:

0.236

AC:

3557

AN:

15096

Ashkenazi Jewish (ASJ)

AF:

0.328

AC:

1114

AN:

3394

East Asian (EAS)

AF:

0.00290

AC:

AN:

5176

South Asian (SAS)

AF:

0.164

AC:

784

AN:

4766

European-Finnish (FIN)

AF:

0.343

AC:

3547

AN:

10330

Middle Eastern (MID)

AF:

0.278

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.389

AC:

25617

AN:

65876

Other (OTH)

AF:

0.296

AC:

615

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

1374

2749

4123

5498

6872

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

440

880

1320

1760

2200

<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:

0.356

Hom.:

4037

EpiCase

AF:

0.400

EpiControl

AF:

0.398

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

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: 40.459% in gnomAD_Exomes) 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.A synonymous variant not located in a splice region. -

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.063

(source)

DANN

Benign

0.14

PhyloP100

-3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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