rs118203907

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_000130.5(F5):c.5189A>G(p.Tyr1730Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

F5
NM_000130.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.58

Publications

8 publications found

Variant links:

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

F5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 1-169530805-T-C is Pathogenic according to our data. Variant chr1-169530805-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F5	NM_000130.5 link	c.5189A>G	p.Tyr1730Cys	missense_variant	Exon 15 of 25	ENST00000367797.9	NP_000121.2	P12259

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F5	ENST00000367797.9 link	c.5189A>G	p.Tyr1730Cys	missense_variant	Exon 15 of 25	1	NM_000130.5	ENSP00000356771.3		P12259
F5	ENST00000367796.3 link	c.5204A>G	p.Tyr1735Cys	missense_variant	Exon 15 of 25	5		ENSP00000356770.3		A0A0A0MRJ7

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

250750

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461556

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727084

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1111770

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000345

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Factor V deficiency

Pathogenic:2

Jan 11, 2019

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The F5 c.5189A>G (p.Tyr1730Cys) missense variant, also referred to as p.Tyr1702Cys in the literature, has been reported in four studies in which it is found in a total of seven individuals with factor V deficiency and FV:C levels <1-2%, including in four in a homozygous state, in two in a compound heterozygous state, and in one in a heterozygous state in whom a second variant was not identified (Castoldi et al. 2001; Montefusco et al. 2003; Yamakage et al. 2006; Talbot et al. 2010). Two of the homozygous individuals remained asymptomatic. The p.Tyr1730Cys variant is also found in three symptomatic individuals with FV:C levels of between 30-60%, including one individual with digenic variants (Castoldi et al. 2000; Castoldi et al. 2001). The p.Tyr1730Cys variant was reported in one of 200 control individuals who showed reduced FV levels (FV:c 58%). This variant is reported at a frequency of 0.000036 in the European (non-Finnish) population of the Genome Aggregation Database. Castoldi et al. (2000) noted a lack of expression of the p.Tyr1730Cys variant protein in the plasma of an affected individual while FV activity in plasma of carriers was reported at 65% (Yamakage et al. 2006). Additionally, functional studies in COS-1 cells demonstrate significantly impaired secretion and inadequate FV procoagulant activity of mutant protein as compared to the wildtype protein (Yamakage et al. 2006). The Tyr1730 residue is highly conserved and X-ray crystal structure analysis suggest that this residue may play an important role in maintaining the structure and function of the FV molecule. Based on the collective evidence the p.Tyr1730Cys variant is classified as pathogenic for factor V deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Jul 15, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Congenital factor V deficiency

Pathogenic:1

Sep 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is also known as p.Tyr1702Cys. For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt F5 protein function. ClinVar contains an entry for this variant (Variation ID: 649). This missense change has been observed in individual(s) with factor V deficiency (PMID: 10942390, 11418372, 16476093, 24517203). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs118203907, gnomAD 0.004%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1730 of the F5 protein (p.Tyr1730Cys). -

not provided

Pathogenic:1

Apr 18, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect: significantly decreased protein level and activity (PMID: 16476093); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.5279A>G p.Y1702C; This variant is associated with the following publications: (PMID: 11435304, 11418372, 12816860, 20735394, 24517203, 16476093, 10942390) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;D

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.3

H;.

PhyloP100

7.6

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-8.0

D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.89

MutPred

0.89

Loss of phosphorylation at Y1730 (P = 0.084);.;

MVP

0.97

MPC

0.53

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.99

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

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

Publications

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rs118203907

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over