rs9332607

Variant names:

• chr1-169540995-G-A
• rs9332607
• NM_000130.5:c.4095C>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.4095C>T​(p.Thr1365Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 1,609,928 control chromosomes in the GnomAD database, including 119,203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6316 hom., cov: 31)
  • Exomes 𝑓: 0.38 (112887 hom.)
• Consequence: F5 NM_000130.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:9
• Conservation: PhyloP100: -3.62
• Publications: 7 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 1-169540995-G-A is Benign according to our data. Variant chr1-169540995-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.62 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.385 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.4095C>T	p.Thr1365Thr	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.4095C>T	p.Thr1365Thr	synonymous	Exon 13 of 25	ENSP00000356771.3	P12259
	F5	ENST00000367796.3	TSL:5	c.4110C>T	p.Thr1370Thr	synonymous	Exon 13 of 25	ENSP00000356770.3	A0A0A0MRJ7
	F5	ENST00000904428.1		c.1611+8806C>T		intron	N/A	ENSP00000574487.1

Frequencies

GnomAD3 genomes AF: 0.289 AC: 42938 AN: 148770 Hom.: 6316 Cov.: 31

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.343

Gnomad MID AF: 0.274

Gnomad NFE AF: 0.389

Gnomad OTH AF: 0.300

GnomAD2 exomes AF: 0.294 AC: 73699 AN: 250494 AF XY: 0.299

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.345

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.368

Gnomad NFE exome AF: 0.405

Gnomad OTH exome AF: 0.325

GnomAD4 exome AF: 0.379 AC: 553539 AN: 1461038 Hom.: 112887 Cov.: 107 AF XY: 0.374 AC XY: 271948 AN XY: 726818

African (AFR) AF: 0.181 AC: 6061 AN: 33458

American (AMR) AF: 0.182 AC: 8108 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 9130 AN: 26104

East Asian (EAS) AF: 0.000605 AC: 24 AN: 39678

South Asian (SAS) AF: 0.187 AC: 16146 AN: 86170

European-Finnish (FIN) AF: 0.366 AC: 19540 AN: 53412

Middle Eastern (MID) AF: 0.304 AC: 1755 AN: 5764

European-Non Finnish (NFE) AF: 0.425 AC: 471863 AN: 1111548

Other (OTH) AF: 0.347 AC: 20912 AN: 60342

GnomAD4 genome AF: 0.288 AC: 42938 AN: 148890 Hom.: 6316 Cov.: 31 AF XY: 0.281 AC XY: 20454 AN XY: 72864

African (AFR) AF: 0.175 AC: 7177 AN: 41038

American (AMR) AF: 0.236 AC: 3557 AN: 15096

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1114 AN: 3394

East Asian (EAS) AF: 0.00290 AC: 15 AN: 5176

South Asian (SAS) AF: 0.164 AC: 784 AN: 4766

European-Finnish (FIN) AF: 0.343 AC: 3547 AN: 10330

Middle Eastern (MID) AF: 0.278 AC: 80 AN: 288

European-Non Finnish (NFE) AF: 0.389 AC: 25617 AN: 65876

Other (OTH) AF: 0.296 AC: 615 AN: 2078

Alfa AF: 0.356 Hom.: 4037

EpiCase AF: 0.400

EpiControl AF: 0.398

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	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	0.063
DANN	Benign	0.14
PhyloP100		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs9332607; hg19: chr1-169510233; COSMIC: COSV63123403;