rs6024

Variant names:

• chr1-169542801-T-C
• rs6024
• NM_000130.5:c.2289A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000130.5(F5):​c.2289A>G​(p.Glu763Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0611 in 1,614,122 control chromosomes in the GnomAD database, including 3,539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (357 hom., cov: 32)
  • Exomes 𝑓: 0.062 (3182 hom.)
• Consequence: F5 NM_000130.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.153
• Publications: 12 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-169542801-T-C is Benign according to our data. Variant chr1-169542801-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.153 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.098 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.2289A>G	p.Glu763Glu	synonymous	Exon 13 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.2289A>G	p.Glu763Glu	synonymous	Exon 13 of 25	ENSP00000356771.3	P12259
	F5	ENST00000367796.3	TSL:5	c.2304A>G	p.Glu768Glu	synonymous	Exon 13 of 25	ENSP00000356770.3	A0A0A0MRJ7
	F5	ENST00000904428.1		c.1611+7000A>G		intron	N/A	ENSP00000574487.1

Frequencies

GnomAD3 genomes AF: 0.0549 AC: 8362 AN: 152182 Hom.: 356 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.0752

Gnomad EAS AF: 0.0300

Gnomad SAS AF: 0.0735

Gnomad FIN AF: 0.0836

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0664

Gnomad OTH AF: 0.0670

GnomAD2 exomes AF: 0.0654 AC: 16420 AN: 251174 AF XY: 0.0662

Gnomad AFR exome AF: 0.00898

Gnomad AMR exome AF: 0.0957

Gnomad ASJ exome AF: 0.0699

Gnomad EAS exome AF: 0.0303

Gnomad FIN exome AF: 0.0855

Gnomad NFE exome AF: 0.0628

Gnomad OTH exome AF: 0.0740

GnomAD4 exome AF: 0.0618 AC: 90301 AN: 1461822 Hom.: 3182 Cov.: 48 AF XY: 0.0626 AC XY: 45531 AN XY: 727218

African (AFR) AF: 0.00908 AC: 304 AN: 33472

American (AMR) AF: 0.0962 AC: 4301 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0705 AC: 1843 AN: 26134

East Asian (EAS) AF: 0.0599 AC: 2380 AN: 39700

South Asian (SAS) AF: 0.0738 AC: 6364 AN: 86256

European-Finnish (FIN) AF: 0.0835 AC: 4458 AN: 53418

Middle Eastern (MID) AF: 0.0891 AC: 514 AN: 5768

European-Non Finnish (NFE) AF: 0.0597 AC: 66399 AN: 1111958

Other (OTH) AF: 0.0619 AC: 3738 AN: 60396

GnomAD4 genome AF: 0.0549 AC: 8364 AN: 152300 Hom.: 357 Cov.: 32 AF XY: 0.0572 AC XY: 4262 AN XY: 74468

African (AFR) AF: 0.0110 AC: 459 AN: 41574

American (AMR) AF: 0.102 AC: 1562 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0752 AC: 261 AN: 3472

East Asian (EAS) AF: 0.0301 AC: 156 AN: 5186

South Asian (SAS) AF: 0.0736 AC: 355 AN: 4824

European-Finnish (FIN) AF: 0.0836 AC: 887 AN: 10616

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0664 AC: 4516 AN: 68022

Other (OTH) AF: 0.0668 AC: 141 AN: 2112

Alfa AF: 0.0629 Hom.: 251

Bravo AF: 0.0514

Asia WGS AF: 0.0630 AC: 218 AN: 3478

EpiCase AF: 0.0628

EpiControl AF: 0.0635

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.52
DANN	Benign	0.46
PhyloP100		-0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs6024; hg19: chr1-169512039; COSMIC: COSV63127429;