rs6030

Positions:

chr1-169529737-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_000130.5(F5):c.5290A>G(p.Met1764Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,613,296 control chromosomes in the GnomAD database, including 89,570 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.30 ( 7249 hom., cov: 32)

Exomes 𝑓: 0.33 ( 82321 hom. )

Consequence

F5
NM_000130.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -2.27

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.3938546E-4).

BP6

Variant 1-169529737-T-C is Benign according to our data. Variant chr1-169529737-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255210.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=4}. Variant chr1-169529737-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F5	NM_000130.5 linkuse as main transcript	c.5290A>G	p.Met1764Val	missense_variant	16/25	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.5290A>G	p.Met1764Val	missense_variant	16/25	1	NM_000130.5	ENSP00000356771.3		P12259
F5	ENST00000367796.3 linkuse as main transcript	c.5305A>G	p.Met1769Val	missense_variant	16/25	5		ENSP00000356770.3		A0A0A0MRJ7

Frequencies

GnomAD3 genomes

AF:

0.299

AC:

45508

AN:

151956

Hom.:

7240

Cov.:

show subpopulations

Gnomad AFR

AF:

0.197

Gnomad AMI

AF:

0.192

Gnomad AMR

AF:

0.440

Gnomad ASJ

AF:

0.241

Gnomad EAS

AF:

0.270

Gnomad SAS

AF:

0.400

Gnomad FIN

AF:

0.290

Gnomad MID

AF:

0.323

Gnomad NFE

AF:

0.330

Gnomad OTH

AF:

0.330

GnomAD3 exomes

AF:

0.343

AC:

86072

AN:

250926

Hom.:

15869

AF XY:

0.344

AC XY:

46576

AN XY:

135588

show subpopulations

Gnomad AFR exome

AF:

0.192

Gnomad AMR exome

AF:

0.510

Gnomad ASJ exome

AF:

0.245

Gnomad EAS exome

AF:

0.258

Gnomad SAS exome

AF:

0.406

Gnomad FIN exome

AF:

0.294

Gnomad NFE exome

AF:

0.328

Gnomad OTH exome

AF:

0.353

GnomAD4 exome

AF:

0.332

AC:

485070

AN:

1461222

Hom.:

82321

Cov.:

AF XY:

0.334

AC XY:

242557

AN XY:

726920

show subpopulations

Gnomad4 AFR exome

AF:

0.191

Gnomad4 AMR exome

AF:

0.504

Gnomad4 ASJ exome

AF:

0.243

Gnomad4 EAS exome

AF:

0.297

Gnomad4 SAS exome

AF:

0.402

Gnomad4 FIN exome

AF:

0.296

Gnomad4 NFE exome

AF:

0.329

Gnomad4 OTH exome

AF:

0.322

GnomAD4 genome

AF:

0.299

AC:

45534

AN:

152074

Hom.:

7249

Cov.:

AF XY:

0.304

AC XY:

22571

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.196

Gnomad4 AMR

AF:

0.441

Gnomad4 ASJ

AF:

0.241

Gnomad4 EAS

AF:

0.270

Gnomad4 SAS

AF:

0.401

Gnomad4 FIN

AF:

0.290

Gnomad4 NFE

AF:

0.331

Gnomad4 OTH

AF:

0.327

Alfa

AF:

0.327

Hom.:

20077

Bravo

AF:

0.305

TwinsUK

AF:

0.322

AC:

1193

ALSPAC

AF:

0.333

AC:

1285

ESP6500AA

AF:

0.199

AC:

878

ESP6500EA

AF:

0.336

AC:

2886

ExAC

AF:

0.335

AC:

40667

Asia WGS

AF:

0.344

AC:

1195

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	This variant is associated with the following publications: (PMID: 22353194, 17640947, 20981092, 16542711) -

Thrombophilia due to activated protein C resistance

Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Congenital factor V deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.012

DANN

Benign

0.70

DEOGEN2

Benign

0.012

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.032

T;T

MetaRNN

Benign

0.00014

T;T

MetaSVM

Benign

-0.43

MutationAssessor

Benign

-1.2

N;.

PrimateAI

Benign

0.20

PROVEAN

Benign

0.77

N;N

REVEL

Benign

0.23

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.0060

MPC

0.087

ClinPred

0.0039

GERP RS

-2.9

Varity_R

0.11

gMVP

0.58

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