rs118203907

Positions:

chr1-169530805-T-C

Variant summary

Our verdict is Pathogenic. Variant got 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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. Variant chr1-169530805-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F5	NM_000130.5 linkuse as main transcript	c.5189A>G	p.Tyr1730Cys	missense_variant	15/25	ENST00000367797.9	NP_000121.2	P12259

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F5	ENST00000367797.9 linkuse as main transcript	c.5189A>G	p.Tyr1730Cys	missense_variant	15/25	1	NM_000130.5	ENSP00000356771.3		P12259
F5	ENST00000367796.3 linkuse as main transcript	c.5204A>G	p.Tyr1735Cys	missense_variant	15/25	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

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250750

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135488

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 15, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 11, 2019	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. -

Congenital factor V deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 03, 2023

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). This variant is present in population databases (rs118203907, gnomAD 0.004%). 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 also known as p.Tyr1702Cys. ClinVar contains an entry for this variant (Variation ID: 649). 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. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 18, 2024

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

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;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over