rs1801711

Variant names:

• chr1-169549811-C-T
• rs6025
• NM_000130.5:c.1601G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-169549811-C-T
• chr1-169549811-C-A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 4P and 9B. PS3 BP4_Strong BS1_Supporting BS2

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 frequency of 0.0214 in 1,613,166 control chromosomes in the GnomAD database, including 450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). 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.

• Frequency:
  • Genomes: 𝑓 0.017 (37 hom., cov: 32)
  • Exomes 𝑓: 0.022 (413 hom.)
• Consequence: F5 NM_000130.5 missense
• Clinical Significance: drug response reviewed by expert panel P:21 U:1 B:1 O:6
• Conservation: PhyloP100: 3.48
• Publications: 1621 publications found

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, ClinGen, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: 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 support a benign effect (MetaRNN=0.007941633).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0173 (2635/152318) while in subpopulation NFE AF = 0.0263 (1787/68026). AF 95% confidence interval is 0.0253. There are 37 homozygotes in GnomAd4. There are 1248 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 37 AR,AD gene

Variant Effect in Transcripts

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

Sel.	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.: 37 Cov.: 32

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.: 31 AF XY: 0.0218 AC XY: 15857 AN XY: 726812

African (AFR) AF: 0.00290 AC: 97 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: 3 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

GnomAD4 genome AF: 0.0173 AC: 2635 AN: 152318 Hom.: 37 Cov.: 32 AF XY: 0.0168 AC XY: 1248 AN XY: 74472

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: 69 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0122 AC: 59 AN: 4834

European-Finnish (FIN) AF: 0.0234 AC: 248 AN: 10616

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0263 AC: 1787 AN: 68026

Other (OTH) AF: 0.0199 AC: 42 AN: 2114

Alfa AF: 0.0238 Hom.: 146

Bravo AF: 0.0167

ClinVar

ClinVar submissions

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	-	1	Thrombophilia due to activated protein C resistance (11)
3	-	-	not provided (3)
2	-	-	Congenital factor V deficiency (3)
2	-	-	Factor V deficiency (3)
1	-	-	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)
1	-	-	Inborn genetic diseases (1)
1	-	-	not specified (1)
-	1	-	Susceptibility to severe coronavirus disease (COVID-19) due to an impaired coagulation process (1)
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	28
DEOGEN2	Benign	0.31	T
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0079	T
PhyloP100		3.5
Sift4G	Uncertain	0.014	D
Vest4		0.20
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

Other links and lift over

dbSNP: rs6025; hg19: chr1-169519049;