1-169542317-T-C

Variant names:

• chr1-169542317-T-C
• rs6032
• NM_000130.5:c.2773A>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.2773A>G​(p.Lys925Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,613,780 control chromosomes in the GnomAD database, including 60,109 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4743 hom., cov: 31)
  • Exomes 𝑓: 0.27 (55366 hom.)
• Consequence: F5 NM_000130.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.376
• Publications: 45 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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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=0.0026506782).
• BP6: Variant 1-169542317-T-C is Benign according to our data. Variant chr1-169542317-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.334 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F5	NM_000130.5	MANE Select	c.2773A>G	p.Lys925Glu	missense	Exon 13 of 25	NP_000121.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F5	ENST00000367797.9	TSL:1 MANE Select	c.2773A>G	p.Lys925Glu	missense	Exon 13 of 25	ENSP00000356771.3
	F5	ENST00000367796.3	TSL:5	c.2788A>G	p.Lys930Glu	missense	Exon 13 of 25	ENSP00000356770.3

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37254 AN: 151954 Hom.: 4731 Cov.: 31

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.261

GnomAD2 exomes AF: 0.279 AC: 69910 AN: 251014 AF XY: 0.278

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.415

Gnomad ASJ exome AF: 0.177

Gnomad EAS exome AF: 0.221

Gnomad FIN exome AF: 0.213

Gnomad NFE exome AF: 0.268

Gnomad OTH exome AF: 0.285

GnomAD4 exome AF: 0.272 AC: 397264 AN: 1461708 Hom.: 55366 Cov.: 64 AF XY: 0.273 AC XY: 198289 AN XY: 727160

African (AFR) AF: 0.180 AC: 6014 AN: 33474

American (AMR) AF: 0.409 AC: 18273 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 4594 AN: 26136

East Asian (EAS) AF: 0.226 AC: 8990 AN: 39698

South Asian (SAS) AF: 0.325 AC: 28070 AN: 86250

European-Finnish (FIN) AF: 0.217 AC: 11597 AN: 53414

Middle Eastern (MID) AF: 0.273 AC: 1575 AN: 5768

European-Non Finnish (NFE) AF: 0.272 AC: 302218 AN: 1111866

Other (OTH) AF: 0.264 AC: 15933 AN: 60394

GnomAD4 genome AF: 0.245 AC: 37295 AN: 152072 Hom.: 4743 Cov.: 31 AF XY: 0.247 AC XY: 18356 AN XY: 74356

African (AFR) AF: 0.183 AC: 7590 AN: 41492

American (AMR) AF: 0.342 AC: 5212 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 581 AN: 3466

East Asian (EAS) AF: 0.234 AC: 1211 AN: 5172

South Asian (SAS) AF: 0.323 AC: 1559 AN: 4820

European-Finnish (FIN) AF: 0.211 AC: 2241 AN: 10602

Middle Eastern (MID) AF: 0.233 AC: 68 AN: 292

European-Non Finnish (NFE) AF: 0.267 AC: 18110 AN: 67950

Other (OTH) AF: 0.260 AC: 549 AN: 2114

Alfa AF: 0.262 Hom.: 13007

Bravo AF: 0.254

TwinsUK AF: 0.270 AC: 1000

ALSPAC AF: 0.280 AC: 1080

ESP6500AA AF: 0.184 AC: 812

ESP6500EA AF: 0.274 AC: 2355

ExAC AF: 0.274 AC: 33213

Asia WGS AF: 0.283 AC: 983 AN: 3478

EpiCase AF: 0.269

EpiControl AF: 0.270

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	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	Thrombophilia due to thrombin defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.062
DANN	Benign	0.24
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00071	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.51	N
PhyloP100		-0.38
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.42	N
REVEL	Benign	0.077
Sift	Benign	1.0	T
Sift4G	Benign	0.99	T
Polyphen		0.0	B
Vest4		0.038
MPC		0.12
ClinPred		0.0040	T
GERP RS		-5.1
Varity_R		0.040
gMVP		0.19
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: rs6032; hg19: chr1-169511555; COSMIC: COSV63120680;