rs9332695

Variant names:

• chr1-169542347-T-A
• rs9332695
• NM_000130.5:c.2743A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000130.5(F5):​c.2743A>T​(p.Thr915Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,600,770 control chromosomes in the GnomAD database, including 239 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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. T915T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (28 hom., cov: 32)
  • Exomes 𝑓: 0.015 (211 hom.)
• Consequence: F5 NM_000130.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.125
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025451481).
• BP6: Variant 1-169542347-T-A is Benign according to our data. Variant chr1-169542347-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 293619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0129 (1965/152168) while in subpopulation NFE AF = 0.0159 (1079/67974). AF 95% confidence interval is 0.0151. There are 28 homozygotes in GnomAd4. There are 1014 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AR,AD gene

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.2743A>T	p.Thr915Ser	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.2743A>T	p.Thr915Ser	missense	Exon 13 of 25	ENSP00000356771.3	P12259
	F5	ENST00000367796.3	TSL:5	c.2758A>T	p.Thr920Ser	missense	Exon 13 of 25	ENSP00000356770.3	A0A0A0MRJ7
	F5	ENST00000904428.1		c.1611+7454A>T		intron	N/A	ENSP00000574487.1

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1966 AN: 152050 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.0879

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00436

Gnomad FIN AF: 0.0381

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.0136 AC: 3405 AN: 250998 AF XY: 0.0138

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.00787

Gnomad ASJ exome AF: 0.0259

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0398

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.0159

GnomAD4 exome AF: 0.0150 AC: 21724 AN: 1448602 Hom.: 211 Cov.: 68 AF XY: 0.0146 AC XY: 10509 AN XY: 720696

African (AFR) AF: 0.00234 AC: 78 AN: 33280

American (AMR) AF: 0.00876 AC: 386 AN: 44084

Ashkenazi Jewish (ASJ) AF: 0.0275 AC: 714 AN: 25996

East Asian (EAS) AF: 0.00 AC: 0 AN: 39530

South Asian (SAS) AF: 0.00346 AC: 295 AN: 85182

European-Finnish (FIN) AF: 0.0344 AC: 1832 AN: 53224

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5736

European-Non Finnish (NFE) AF: 0.0159 AC: 17520 AN: 1101648

Other (OTH) AF: 0.0149 AC: 890 AN: 59922

GnomAD4 genome AF: 0.0129 AC: 1965 AN: 152168 Hom.: 28 Cov.: 32 AF XY: 0.0136 AC XY: 1014 AN XY: 74406

African (AFR) AF: 0.00274 AC: 114 AN: 41540

American (AMR) AF: 0.00981 AC: 150 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 99 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4814

European-Finnish (FIN) AF: 0.0381 AC: 404 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0159 AC: 1079 AN: 67974

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.0143 Hom.: 5

Bravo AF: 0.0109

TwinsUK AF: 0.0181 AC: 67

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0170 AC: 146

ExAC AF: 0.0129 AC: 1560

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0152

EpiControl AF: 0.0149

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.70
DANN	Benign	0.094
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.13
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.034
Sift	Benign	0.76	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.057
MutPred		0.076		Gain of glycosylation at T915 (P = 0.0235)
MPC		0.22
ClinPred		0.00042	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.099
gMVP		0.17
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: rs9332695; hg19: chr1-169511585; COSMIC: COSV99057296;