NM_000130.5:c.405G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000130.5(F5):c.405G>A(p.Ala135Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,612,154 control chromosomes in the GnomAD database, including 45,051 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 8966 hom., cov: 31)

Exomes 𝑓: 0.20 ( 36085 hom. )

Consequence

F5
NM_000130.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.79

Publications

28 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 -16 ACMG points.

BP6

Variant 1-169560735-C-T is Benign according to our data. Variant chr1-169560735-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F5	NM_000130.5 link	c.405G>A	p.Ala135Ala	synonymous_variant	Exon 4 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.405G>A	p.Ala135Ala	synonymous_variant	Exon 4 of 25	1	NM_000130.5	ENSP00000356771.3		P12259
F5	ENST00000367796.3 link	c.405G>A	p.Ala135Ala	synonymous_variant	Exon 4 of 25	5		ENSP00000356770.3		A0A0A0MRJ7

Frequencies

GnomAD3 genomes

AF:

0.304

AC:

46101

AN:

151608

Hom.:

8956

Cov.:

show subpopulations

Gnomad AFR

AF:

0.518

Gnomad AMI

AF:

0.0879

Gnomad AMR

AF:

0.285

Gnomad ASJ

AF:

0.205

Gnomad EAS

AF:

0.652

Gnomad SAS

AF:

0.194

Gnomad FIN

AF:

0.255

Gnomad MID

AF:

0.163

Gnomad NFE

AF:

0.177

Gnomad OTH

AF:

0.285

GnomAD2 exomes

AF:

0.257

AC:

64502

AN:

251236

AF XY:

0.245

show subpopulations

Gnomad AFR exome

AF:

0.525

Gnomad AMR exome

AF:

0.267

Gnomad ASJ exome

AF:

0.211

Gnomad EAS exome

AF:

0.679

Gnomad FIN exome

AF:

0.255

Gnomad NFE exome

AF:

0.174

Gnomad OTH exome

AF:

0.235

GnomAD4 exome

AF:

0.200

AC:

292195

AN:

1460430

Hom.:

36085

Cov.:

AF XY:

0.198

AC XY:

143756

AN XY:

726508

show subpopulations

African (AFR)

AF:

0.530

AC:

17708

AN:

33412

American (AMR)

AF:

0.271

AC:

12087

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.210

AC:

5479

AN:

26102

East Asian (EAS)

AF:

0.600

AC:

23818

AN:

39694

South Asian (SAS)

AF:

0.175

AC:

15048

AN:

86206

European-Finnish (FIN)

AF:

0.257

AC:

13722

AN:

53420

Middle Eastern (MID)

AF:

0.213

AC:

1094

AN:

5144

European-Non Finnish (NFE)

AF:

0.170

AC:

188648

AN:

1111504

Other (OTH)

AF:

0.242

AC:

14591

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

12500

24999

37499

49998

62498

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7010

14020

21030

28040

35050

<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:

0.304

AC:

46142

AN:

151724

Hom.:

8966

Cov.:

AF XY:

0.306

AC XY:

22699

AN XY:

74120

show subpopulations

African (AFR)

AF:

0.518

AC:

21427

AN:

41376

American (AMR)

AF:

0.284

AC:

4327

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.205

AC:

711

AN:

3464

East Asian (EAS)

AF:

0.651

AC:

3321

AN:

5102

South Asian (SAS)

AF:

0.193

AC:

924

AN:

4788

European-Finnish (FIN)

AF:

0.255

AC:

2692

AN:

10540

Middle Eastern (MID)

AF:

0.169

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.177

AC:

12004

AN:

67912

Other (OTH)

AF:

0.288

AC:

607

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1440

2880

4319

5759

7199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

428

856

1284

1712

2140

<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:

0.227

Hom.:

15000

Bravo

AF:

0.319

Asia WGS

AF:

0.447

AC:

1554

AN:

3478

EpiCase

AF:

0.173

EpiControl

AF:

0.175

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

-0.58

CADD

Benign

(source)

DANN

Benign

0.51

PhyloP100

-2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.42

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.42

Position offset: -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