NM_000130.5:c.6443T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000130.5(F5):c.6443T>C(p.Met2148Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0422 in 1,613,552 control chromosomes in the GnomAD database, including 1,811 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 124 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1687 hom. )

Consequence

F5
NM_000130.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.76

Publications

30 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012470007).

BP6

Variant 1-169515529-A-G is Benign according to our data. Variant chr1-169515529-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F5	NM_000130.5 link	c.6443T>C	p.Met2148Thr	missense_variant	Exon 24 of 25	ENST00000367797.9	NP_000121.2	P12259

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
F5	ENST00000367797.9 link	c.6443T>C	p.Met2148Thr	missense_variant	Exon 24 of 25	1	NM_000130.5	ENSP00000356771.3	P12259
F5	ENST00000367796.3 link	c.6458T>C	p.Met2153Thr	missense_variant	Exon 24 of 25	5		ENSP00000356770.3	A0A0A0MRJ7
F5	ENST00000495481.1 link	n.217T>C		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0305

AC:

4632

AN:

152044

Hom.:

124

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00858

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.0147

Gnomad ASJ

AF:

0.0181

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0139

Gnomad FIN

AF:

0.0392

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0504

Gnomad OTH

AF:

0.0215

GnomAD2 exomes

AF:

0.0303

AC:

7611

AN:

251034

AF XY:

0.0308

show subpopulations

Gnomad AFR exome

AF:

0.00806

Gnomad AMR exome

AF:

0.0128

Gnomad ASJ exome

AF:

0.0191

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0409

Gnomad NFE exome

AF:

0.0471

Gnomad OTH exome

AF:

0.0299

GnomAD4 exome

AF:

0.0434

AC:

63460

AN:

1461390

Hom.:

1687

Cov.:

AF XY:

0.0427

AC XY:

31062

AN XY:

727012

show subpopulations

African (AFR)

AF:

0.00670

AC:

224

AN:

33448

American (AMR)

AF:

0.0128

AC:

573

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.0188

AC:

491

AN:

26104

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39690

South Asian (SAS)

AF:

0.0149

AC:

1288

AN:

86256

European-Finnish (FIN)

AF:

0.0418

AC:

2232

AN:

53374

Middle Eastern (MID)

AF:

0.00763

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0506

AC:

56226

AN:

1111678

Other (OTH)

AF:

0.0394

AC:

2380

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

3748

7496

11245

14993

18741

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2082

4164

6246

8328

10410

<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:

0.0304

AC:

4630

AN:

152162

Hom.:

124

Cov.:

AF XY:

0.0281

AC XY:

2091

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.00855

AC:

355

AN:

41520

American (AMR)

AF:

0.0146

AC:

223

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0181

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.0139

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0392

AC:

415

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0504

AC:

3423

AN:

67982

Other (OTH)

AF:

0.0213

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

226

451

677

902

1128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0409

Hom.:

387

Bravo

AF:

0.0278

TwinsUK

AF:

0.0537

AC:

199

ALSPAC

AF:

0.0503

AC:

194

ESP6500AA

AF:

0.0104

AC:

ESP6500EA

AF:

0.0447

AC:

384

ExAC

AF:

0.0305

AC:

3707

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.0400

EpiControl

AF:

0.0435

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

PreventionGenetics, part of Exact Sciences

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

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

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

D;T

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.83

T;T

MetaRNN

Benign

0.012

T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.8

L;.

PhyloP100

3.8

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.012

D;D

Polyphen

1.0

D;.

Vest4

0.45

MPC

0.50

ClinPred

0.022

GERP RS

5.6

Varity_R

0.78

gMVP

0.84

Mutation Taster

=89/11

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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