F5 p.Arg534Gln

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is The variant received -4 classification points (ACMG Germline Pathogenicity v2019): 4P and 8B. PS3BS1BP4_Strong

The NM_000130.5(F5):c.1601G>A (p.Arg534Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0214 (AC=34,574) in the gnomAD database across 1,613,166 control chromosomes, including 450 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.034. In-silico predictor (AlphaMissense) classifies this variant as likely benign. Variant has been reported in ClinVar as Uncertain Significance (★★★). ClinVar reports functional evidence for this variant: "SCV000538025: This missense variant destroys one of three APC cleavage sites in factor V, rendering the protein resistant to APC inactivation. GeneReviews: Kujovich et al., 2010, http://www.ncbi.nlm.nih.gov/books/NBK1368/)." and additional evidence is available in ClinVar. This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Thrombophilia due to activated protein c resistance (thph2).

Frequency

Genomes: 𝑓 0.017 ( 37 hom., cov: 32)

Exomes 𝑓: 0.022 ( 413 hom. )

Consequence

F5
NM_000130.5 missense

Scores

Clinical Significance

drug response reviewed by expert panel P:26U:1B:1O:6

Conservation

PhyloP100: 3.48

Publications

1621 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia
congenital factor V deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
East Texas bleeding disorder
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

F5 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000130.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 points.

PS3

Well-established functional study supports damaging effect (PS3); SCV000538025: This missense variant destroys one of three APC cleavage sites in factor V, rendering the protein resistant to APC inactivation. GeneReviews: Kujovich et al., 2010, http://www.ncbi.nlm.nih.gov/books/NBK1368/).; SCV002754531: Functional studies have shown that this variant alters factor V protein function (PMID: 11110695, 20051284, 22704462, 26251307) (PS3).; SCV007096568: The p.(Arg534Gln) variant eliminates the APC cleavage site, resulting in resistance to APC inactivation of factor V, leading to more thrombin generation (PMID: 30297698).; SCV000728219: Published studies demonstrate a deleterious effect on protein function (Nicolaes et al., 1995; Pezeshkpoor et al., 2016); SCV000262346: Experimental studies have shown that this missense change affects F5 function (PMID: 7910348, 7911872).

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); No splicing predictor data available.; Germline computational verdict: benign (Strong).

BS1

GnomAD effective popmax AF above BS1 threshold — greater than expected for disorder; GnomAD AF = 0.034 exceeds threshold, but 24 reliable P/LP ClinVar submissions — likely a high-frequency founder pathogenic allele; BS1 blocked.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000130.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F5	NM_000130.5	MANE Select	c.1601G>A	p.Arg534Gln	missense	Exon 10 of 25	NP_000121.2	P12259

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
F5	ENST00000367797.9	TSL:1 MANE Select	c.1601G>A	p.Arg534Gln	missense	Exon 10 of 25	ENSP00000356771.3	P12259
F5	ENST00000367796.3	TSL:5	c.1601G>A	p.Arg534Gln	missense	Exon 10 of 25	ENSP00000356770.3	A0A0A0MRJ7
F5	ENST00000904428.1		c.1601G>A	p.Arg534Gln	missense	Exon 10 of 21	ENSP00000574487.1

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

2638

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00446

Gnomad AMI

AF:

0.0932

Gnomad AMR

AF:

0.00929

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0126

Gnomad FIN

AF:

0.0234

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0263

Gnomad OTH

AF:

0.0201

GnomAD4 exome

AF:

0.0219

AC:

31939

AN:

1460848

Hom.:

413

Cov.:

AF XY:

0.0218

AC XY:

15857

AN XY:

726812

show subpopulations

African (AFR)

AF:

0.00290

AC:

AN:

33450

American (AMR)

AF:

0.00711

AC:

318

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0191

AC:

498

AN:

26120

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39666

South Asian (SAS)

AF:

0.0140

AC:

1211

AN:

86234

European-Finnish (FIN)

AF:

0.0212

AC:

1131

AN:

53394

Middle Eastern (MID)

AF:

0.0382

AC:

220

AN:

5766

European-Non Finnish (NFE)

AF:

0.0246

AC:

27360

AN:

1111142

Other (OTH)

AF:

0.0182

AC:

1101

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

Heterozygous variant carriers

1661

3321

4982

6642

8303

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

954

1908

2862

3816

4770

<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:

0.0173

AC:

2635

AN:

152318

Hom.:

Cov.:

AF XY:

0.0168

AC XY:

1248

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00445

AC:

185

AN:

41562

American (AMR)

AF:

0.00928

AC:

142

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0199

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.0122

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0234

AC:

248

AN:

10616

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0263

AC:

1787

AN:

68026

Other (OTH)

AF:

0.0199

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

134

267

401

534

668

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0238

Hom.:

146

Bravo

AF:

0.0167

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.0000410

AC:

AN:

122548

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.000335

AC:

AN:

8960

Hom.:

ABraOM SABE-WGS-1171

AF:

0.0111

AC:

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:drug response

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Thrombophilia due to activated protein C resistance (14)

not provided (4)

Congenital factor V deficiency (4)

Factor V deficiency (3)

Congenital factor V deficiency;C0856761:Budd-Chiari syndrome;C0948008:Ischemic stroke;C1861171:Thrombophilia due to activated protein C resistance;C3280670:Pregnancy loss, recurrent, susceptibility to, 1 (1)

Inborn genetic diseases (1)

not specified (1)

Susceptibility to severe coronavirus disease (COVID-19) due to an impaired coagulation process (1)

Thrombophilia due to activated protein C resistance;C4317320:Factor V deficiency (1)

Budd-Chiari syndrome, susceptibility to (1)

hormonal contraceptives for systemic use response - Toxicity (1)

Ischemic stroke (1)

Pregnancy loss, recurrent, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DEOGEN2

Benign

0.31

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0079

PhyloP100

3.5

Sift4G

Uncertain

0.014

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.79

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over