rs6018

Variant names:

• chr1-169542640-T-G
• rs6018
• NM_000130.5:c.2450A>C

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.2450A>C​(p.Asn817Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0611 in 1,613,968 control chromosomes in the GnomAD database, including 3,539 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.208
• Publications: 38 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, Labcorp Genetics (formerly Invitae), ClinGen
• 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=0.0034109354).
• BP6: Variant 1-169542640-T-G is Benign according to our data. Variant chr1-169542640-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0979 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.2450A>C	p.Asn817Thr	missense	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.2450A>C	p.Asn817Thr	missense	Exon 13 of 25	ENSP00000356771.3	P12259
	F5	ENST00000367796.3	TSL:5	c.2465A>C	p.Asn822Thr	missense	Exon 13 of 25	ENSP00000356770.3	A0A0A0MRJ7
	F5	ENST00000904428.1		c.1611+7161A>C		intron	N/A	ENSP00000574487.1

Frequencies

GnomAD3 genomes AF: 0.0550 AC: 8356 AN: 152026 Hom.: 356 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.0750

Gnomad EAS AF: 0.0299

Gnomad SAS AF: 0.0730

Gnomad FIN AF: 0.0839

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0664

Gnomad OTH AF: 0.0675

GnomAD2 exomes AF: 0.0654 AC: 16423 AN: 251256 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: 0.0742

GnomAD4 exome AF: 0.0618 AC: 90317 AN: 1461824 Hom.: 3182 Cov.: 54 AF XY: 0.0626 AC XY: 45535 AN XY: 727210

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

American (AMR) AF: 0.0962 AC: 4301 AN: 44716

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: 6365 AN: 86258

European-Finnish (FIN) AF: 0.0835 AC: 4458 AN: 53420

Middle Eastern (MID) AF: 0.0893 AC: 515 AN: 5768

European-Non Finnish (NFE) AF: 0.0597 AC: 66414 AN: 1111964

Other (OTH) AF: 0.0619 AC: 3737 AN: 60392

GnomAD4 genome AF: 0.0549 AC: 8358 AN: 152144 Hom.: 357 Cov.: 32 AF XY: 0.0573 AC XY: 4260 AN XY: 74380

African (AFR) AF: 0.0110 AC: 458 AN: 41530

American (AMR) AF: 0.102 AC: 1560 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0750 AC: 260 AN: 3466

East Asian (EAS) AF: 0.0300 AC: 155 AN: 5172

South Asian (SAS) AF: 0.0731 AC: 352 AN: 4816

European-Finnish (FIN) AF: 0.0839 AC: 889 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0664 AC: 4515 AN: 67978

Other (OTH) AF: 0.0673 AC: 142 AN: 2110

Alfa AF: 0.0605 Hom.: 1514

Bravo AF: 0.0514

TwinsUK AF: 0.0542 AC: 201

ALSPAC AF: 0.0532 AC: 205

ESP6500AA AF: 0.00999 AC: 44

ESP6500EA AF: 0.0633 AC: 544

ExAC AF: 0.0617 AC: 7495

Asia WGS AF: 0.0630 AC: 218 AN: 3478

EpiCase AF: 0.0628

EpiControl AF: 0.0635

ClinVar

ClinVar submissions as Germline

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
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	9.1
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.21
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.017
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.020	D
Polyphen		0.068	B
Vest4		0.069
MPC		0.11
ClinPred		0.013	T
GERP RS		2.1
Varity_R		0.079
gMVP		0.24
Mutation Taster		=99/1	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: rs6018; hg19: chr1-169511878; COSMIC: COSV63127421;