rs118203907
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong
The NM_000130.5(F5):āc.5189A>Gā(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 Pathogenic (ā ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 33)
Exomes š: 0.000023 ( 0 hom. )
Consequence
F5
NM_000130.5 missense
NM_000130.5 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 7.58
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]
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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 [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 | UniProt |
---|---|---|---|---|---|---|---|
F5 | NM_000130.5 | c.5189A>G | p.Tyr1730Cys | missense_variant | 15/25 | ENST00000367797.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F5 | ENST00000367797.9 | c.5189A>G | p.Tyr1730Cys | missense_variant | 15/25 | 1 | NM_000130.5 | P2 | |
F5 | ENST00000367796.3 | c.5204A>G | p.Tyr1735Cys | missense_variant | 15/25 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250750Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135488
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GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461556Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15AN XY: 727084
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74358
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Factor V deficiency Pathogenic:2
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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 15, 2001 | - - |
Congenital factor V deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Loss of phosphorylation at Y1730 (P = 0.084);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at