rs6020

Variant names:

• chr1-169549874-C-T
• rs6020
• NM_000130.5:c.1538G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-169549874-C-T
• chr1-169549874-C-A
• chr1-169549874-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000130.5(F5):​c.1538G>A​(p.Arg513Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0539 in 1,613,922 control chromosomes in the GnomAD database, including 14,717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R513R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (2984 hom., cov: 32)
  • Exomes 𝑓: 0.047 (11733 hom.)
• Consequence: F5 NM_000130.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.10
• Publications: 46 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.3489547E-4).
• BP6: Variant 1-169549874-C-T is Benign according to our data. Variant chr1-169549874-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 293628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

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.1538G>A	p.Arg513Lys	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.1538G>A	p.Arg513Lys	missense	Exon 10 of 25	ENSP00000356771.3	P12259
	F5	ENST00000367796.3	TSL:5	c.1538G>A	p.Arg513Lys	missense	Exon 10 of 25	ENSP00000356770.3	A0A0A0MRJ7
	F5	ENST00000904428.1		c.1538G>A	p.Arg513Lys	missense	Exon 10 of 21	ENSP00000574487.1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18830 AN: 152018 Hom.: 2980 Cov.: 32

Gnomad AFR AF: 0.285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0820

Gnomad ASJ AF: 0.0689

Gnomad EAS AF: 0.643

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.0586

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.00920

Gnomad OTH AF: 0.105

GnomAD2 exomes AF: 0.111 AC: 27918 AN: 251418 AF XY: 0.103

Gnomad AFR exome AF: 0.291

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.0610

Gnomad EAS exome AF: 0.652

Gnomad FIN exome AF: 0.0545

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.0693

GnomAD4 exome AF: 0.0466 AC: 68142 AN: 1461784 Hom.: 11733 Cov.: 32 AF XY: 0.0478 AC XY: 34737 AN XY: 727194

African (AFR) AF: 0.290 AC: 9691 AN: 33466

American (AMR) AF: 0.106 AC: 4760 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0568 AC: 1484 AN: 26132

East Asian (EAS) AF: 0.650 AC: 25805 AN: 39684

South Asian (SAS) AF: 0.129 AC: 11096 AN: 86246

European-Finnish (FIN) AF: 0.0521 AC: 2783 AN: 53416

Middle Eastern (MID) AF: 0.0456 AC: 263 AN: 5768

European-Non Finnish (NFE) AF: 0.00668 AC: 7433 AN: 1111958

Other (OTH) AF: 0.0799 AC: 4827 AN: 60390

GnomAD4 genome AF: 0.124 AC: 18859 AN: 152138 Hom.: 2984 Cov.: 32 AF XY: 0.130 AC XY: 9668 AN XY: 74386

African (AFR) AF: 0.284 AC: 11796 AN: 41480

American (AMR) AF: 0.0823 AC: 1258 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0689 AC: 239 AN: 3468

East Asian (EAS) AF: 0.643 AC: 3315 AN: 5158

South Asian (SAS) AF: 0.157 AC: 755 AN: 4822

European-Finnish (FIN) AF: 0.0586 AC: 621 AN: 10592

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.00919 AC: 625 AN: 68006

Other (OTH) AF: 0.111 AC: 235 AN: 2114

Alfa AF: 0.0588 Hom.: 6417

Bravo AF: 0.136

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.268 AC: 1183

ESP6500EA AF: 0.0108 AC: 93

ExAC AF: 0.112 AC: 13593

Asia WGS AF: 0.375 AC: 1302 AN: 3478

EpiCase AF: 0.0108

EpiControl AF: 0.0104

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Budd-Chiari syndrome (1)
-	-	1	Congenital factor V deficiency (1)
-	-	1	Factor V deficiency (1)
-	-	1	Thrombophilia due to activated protein C resistance (1)
-	-	1	Thrombophilia due to thrombin defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.00073	T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	0.92	L
PhyloP100		3.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.44
Sift	Benign	0.25	T
Sift4G	Benign	0.16	T
Polyphen		0.91	P
Vest4		0.19
MPC		0.47
ClinPred		0.018	T
GERP RS		5.7
Varity_R		0.21
gMVP		0.94
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6020; hg19: chr1-169519112; COSMIC: COSV63123547;