NM_000130.5:c.3948C>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.3948C>T(p.Leu1316Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,129,062 control chromosomes in the GnomAD database, including 25,696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 3178 hom., cov: 26)

Exomes 𝑓: 0.13 ( 22518 hom. )

Consequence

F5
NM_000130.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.57

Publications

19 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=-0.86).

BP6

Variant 1-169541142-G-A is Benign according to our data. Variant chr1-169541142-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.57 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F5	NM_000130.5 link	c.3948C>T	p.Leu1316Leu	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.3948C>T	p.Leu1316Leu	synonymous_variant	Exon 13 of 25	1	NM_000130.5	ENSP00000356771.3		P12259
F5	ENST00000367796.3 link	c.3963C>T	p.Leu1321Leu	synonymous_variant	Exon 13 of 25	5		ENSP00000356770.3		A0A0A0MRJ7

Frequencies

GnomAD3 genomes

AF:

0.222

AC:

31944

AN:

144082

Hom.:

3173

Cov.:

show subpopulations

Gnomad AFR

AF:

0.164

Gnomad AMI

AF:

0.173

Gnomad AMR

AF:

0.315

Gnomad ASJ

AF:

0.159

Gnomad EAS

AF:

0.204

Gnomad SAS

AF:

0.286

Gnomad FIN

AF:

0.185

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.243

Gnomad OTH

AF:

0.236

GnomAD2 exomes

AF:

0.208

AC:

42178

AN:

202424

AF XY:

0.209

show subpopulations

Gnomad AFR exome

AF:

0.132

Gnomad AMR exome

AF:

0.305

Gnomad ASJ exome

AF:

0.0943

Gnomad EAS exome

AF:

0.178

Gnomad FIN exome

AF:

0.166

Gnomad NFE exome

AF:

0.214

Gnomad OTH exome

AF:

0.207

GnomAD4 exome

AF:

0.128

AC:

126304

AN:

984884

Hom.:

22518

Cov.:

AF XY:

0.138

AC XY:

68725

AN XY:

498712

show subpopulations

African (AFR)

AF:

0.0794

AC:

2085

AN:

26268

American (AMR)

AF:

0.282

AC:

7844

AN:

27818

Ashkenazi Jewish (ASJ)

AF:

0.0987

AC:

2127

AN:

21554

East Asian (EAS)

AF:

0.166

AC:

5585

AN:

33650

South Asian (SAS)

AF:

0.236

AC:

14976

AN:

63504

European-Finnish (FIN)

AF:

0.176

AC:

8384

AN:

47644

Middle Eastern (MID)

AF:

0.201

AC:

932

AN:

4648

European-Non Finnish (NFE)

AF:

0.109

AC:

78105

AN:

716586

Other (OTH)

AF:

0.145

AC:

6266

AN:

43212

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

7237

14474

21712

28949

36186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

898

1796

2694

3592

4490

<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:

0.222

AC:

31968

AN:

144178

Hom.:

3178

Cov.:

AF XY:

0.223

AC XY:

15705

AN XY:

70352

show subpopulations

African (AFR)

AF:

0.164

AC:

6491

AN:

39550

American (AMR)

AF:

0.315

AC:

4499

AN:

14262

Ashkenazi Jewish (ASJ)

AF:

0.159

AC:

542

AN:

3410

East Asian (EAS)

AF:

0.204

AC:

982

AN:

4804

South Asian (SAS)

AF:

0.286

AC:

1259

AN:

4398

European-Finnish (FIN)

AF:

0.185

AC:

1836

AN:

9942

Middle Eastern (MID)

AF:

0.203

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.243

AC:

15687

AN:

64682

Other (OTH)

AF:

0.235

AC:

466

AN:

1986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

1090

2180

3270

4360

5450

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

344

688

1032

1376

1720

<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:

0.248

Hom.:

1641

Asia WGS

AF:

0.186

AC:

599

AN:

3224

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

May 04, 2021

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

- -

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

-0.86

CADD

Benign

0.71

(source)

DANN

Benign

0.42

PhyloP100

-1.6

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