rs118203906

Positions:

chr1-169555299-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM5PP3_ModeratePP5_ModerateBS1_SupportingBS2_Supporting

The NM_000130.5(F5):c.1001G>C(p.Arg334Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,614,068 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R334G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00013 ( 2 hom. )

Consequence

F5
NM_000130.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 0.301

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 Uncertain_significance. Variant got 4 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-169555300-T-C is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.928

PP5

Variant 1-169555299-C-G is Pathogenic according to our data. Variant chr1-169555299-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 644.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-169555299-C-G is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00013 (190/1461852) while in subpopulation MID AF= 0.00191 (11/5768). AF 95% confidence interval is 0.00107. There are 2 homozygotes in gnomad4_exome. There are 97 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F5	NM_000130.5 linkuse as main transcript	c.1001G>C	p.Arg334Thr	missense_variant	7/25	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.1001G>C	p.Arg334Thr	missense_variant	7/25	1	NM_000130.5	ENSP00000356771.3		P12259
F5	ENST00000367796.3 linkuse as main transcript	c.1001G>C	p.Arg334Thr	missense_variant	7/25	5		ENSP00000356770.3		A0A0A0MRJ7

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000227

AC:

AN:

251352

Hom.:

AF XY:

0.000213

AC XY:

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000130

AC:

190

AN:

1461852

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000556

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000818

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000203

Hom.:

Bravo

AF:

0.000132

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Thrombophilia due to activated protein C resistance

Pathogenic:2Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 15, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Apr 16, 2021	This variant was previously reported in a proximal deep vein thrombosis patient of British origin and was also identified in his mother, who presented with abnormally low APC resistance value. It was not found in 600 other individuals presenting with thromboembolism or in a population of normal blood donors, suggesting that it is a rare factor V variant [PMID: 9454742]. This variant was previously represented as either p.R306T/Arg306Thr or F5 Cambridge in the cited articles. Another missense substitution affecting this residue p. Arg334Gly (referred as Arg306Gly FV Hong Kong) was previously identified in 2 thrombotic patients and 1 nonthrombotic subject of Chinese origin [PMID: 9454741]. Previously this variant was reported to affect the cleavage site responsible for the complete loss of F5 procoagulant activity suggesting its possible contribution to APC resistance [PMID: 30630204, 7989361]. However, invitro recombinant cells harboring this variant revealed intermediate APC resistance patterns between those of wild type factor V and other well-known F5 Leiden (Arg506) variant, suggesting low thrombotic risk association [PMID:12091344]. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.00080

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.15

T;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.79

T;T

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

0.65

MutationAssessor

Benign

2.0

M;.

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.0

D;D

REVEL

Pathogenic

0.66

Sift

Benign

0.14

T;T

Sift4G

Benign

0.68

T;T

Polyphen

0.98

D;.

Vest4

0.67

MVP

0.81

MPC

0.57

ClinPred

0.088

GERP RS

4.8

Varity_R

0.15

gMVP

0.67

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