rs9287090

Variant names:

• chr1-169541142-G-A
• rs9287090
• NM_000130.5:c.3948C>T

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.3948C>T​(p.Leu1316Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,129,062 control chromosomes in the GnomAD database, including 25,696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1316L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.22 (3178 hom., cov: 26)
  • Exomes 𝑓: 0.13 (22518 hom.)
• Consequence: F5 NM_000130.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.57
• Publications: 19 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=-0.86).
• BP6: Variant 1-169541142-G-A is Benign according to our data. Variant chr1-169541142-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.308 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.3948C>T	p.Leu1316Leu	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.3948C>T	p.Leu1316Leu	synonymous	Exon 13 of 25	ENSP00000356771.3	P12259
	F5	ENST00000367796.3	TSL:5	c.3963C>T	p.Leu1321Leu	synonymous	Exon 13 of 25	ENSP00000356770.3	A0A0A0MRJ7
	F5	ENST00000904428.1		c.1611+8659C>T		intron	N/A	ENSP00000574487.1

Frequencies

GnomAD3 genomes AF: 0.222 AC: 31944 AN: 144082 Hom.: 3173 Cov.: 26

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.236

GnomAD2 exomes AF: 0.208 AC: 42178 AN: 202424 AF XY: 0.209

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.305

Gnomad ASJ exome AF: 0.0943

Gnomad EAS exome AF: 0.178

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.207

GnomAD4 exome AF: 0.128 AC: 126304 AN: 984884 Hom.: 22518 Cov.: 90 AF XY: 0.138 AC XY: 68725 AN XY: 498712

African (AFR) AF: 0.0794 AC: 2085 AN: 26268

American (AMR) AF: 0.282 AC: 7844 AN: 27818

Ashkenazi Jewish (ASJ) AF: 0.0987 AC: 2127 AN: 21554

East Asian (EAS) AF: 0.166 AC: 5585 AN: 33650

South Asian (SAS) AF: 0.236 AC: 14976 AN: 63504

European-Finnish (FIN) AF: 0.176 AC: 8384 AN: 47644

Middle Eastern (MID) AF: 0.201 AC: 932 AN: 4648

European-Non Finnish (NFE) AF: 0.109 AC: 78105 AN: 716586

Other (OTH) AF: 0.145 AC: 6266 AN: 43212

GnomAD4 genome AF: 0.222 AC: 31968 AN: 144178 Hom.: 3178 Cov.: 26 AF XY: 0.223 AC XY: 15705 AN XY: 70352

African (AFR) AF: 0.164 AC: 6491 AN: 39550

American (AMR) AF: 0.315 AC: 4499 AN: 14262

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 542 AN: 3410

East Asian (EAS) AF: 0.204 AC: 982 AN: 4804

South Asian (SAS) AF: 0.286 AC: 1259 AN: 4398

European-Finnish (FIN) AF: 0.185 AC: 1836 AN: 9942

Middle Eastern (MID) AF: 0.203 AC: 56 AN: 276

European-Non Finnish (NFE) AF: 0.243 AC: 15687 AN: 64682

Other (OTH) AF: 0.235 AC: 466 AN: 1986

Alfa AF: 0.248 Hom.: 1641

Asia WGS AF: 0.186 AC: 599 AN: 3224

ClinVar

ClinVar submissions

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
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.71
DANN	Benign	0.42
PhyloP100		-1.6
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: rs9287090; hg19: chr1-169510380; COSMIC: COSV63120672;