rs6033

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000130.5(F5):c.1238T>C(p.Met413Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0736 in 1,613,272 control chromosomes in the GnomAD database, including 4,955 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.064 ( 452 hom., cov: 32)

Exomes 𝑓: 0.075 ( 4503 hom. )

Consequence

F5
NM_000130.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.506

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017207563).

BP6

Variant 1-169552615-A-G is Benign according to our data. Variant chr1-169552615-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 255188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169552615-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.104 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.1238T>C	p.Met413Thr	missense_variant	8/25	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.1238T>C	p.Met413Thr	missense_variant	8/25	1	NM_000130.5	ENSP00000356771.3		P12259
F5	ENST00000367796.3 linkuse as main transcript	c.1238T>C	p.Met413Thr	missense_variant	8/25	5		ENSP00000356770.3		A0A0A0MRJ7

Frequencies

GnomAD3 genomes

AF:

0.0644

AC:

9787

AN:

152024

Hom.:

451

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0132

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.108

Gnomad ASJ

AF:

0.0763

Gnomad EAS

AF:

0.0277

Gnomad SAS

AF:

0.0825

Gnomad FIN

AF:

0.116

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0788

Gnomad OTH

AF:

0.0736

GnomAD3 exomes

AF:

0.0756

AC:

19001

AN:

251378

Hom.:

904

AF XY:

0.0772

AC XY:

10494

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.0113

Gnomad AMR exome

AF:

0.0970

Gnomad ASJ exome

AF:

0.0719

Gnomad EAS exome

AF:

0.0294

Gnomad SAS exome

AF:

0.0831

Gnomad FIN exome

AF:

0.115

Gnomad NFE exome

AF:

0.0760

Gnomad OTH exome

AF:

0.0855

GnomAD4 exome

AF:

0.0746

AC:

108957

AN:

1461130

Hom.:

4503

Cov.:

AF XY:

0.0752

AC XY:

54699

AN XY:

726928

show subpopulations

Gnomad4 AFR exome

AF:

0.0108

Gnomad4 AMR exome

AF:

0.0981

Gnomad4 ASJ exome

AF:

0.0720

Gnomad4 EAS exome

AF:

0.0509

Gnomad4 SAS exome

AF:

0.0825

Gnomad4 FIN exome

AF:

0.114

Gnomad4 NFE exome

AF:

0.0739

Gnomad4 OTH exome

AF:

0.0738

GnomAD4 genome

AF:

0.0643

AC:

9785

AN:

152142

Hom.:

452

Cov.:

AF XY:

0.0676

AC XY:

5030

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0132

Gnomad4 AMR

AF:

0.108

Gnomad4 ASJ

AF:

0.0763

Gnomad4 EAS

AF:

0.0276

Gnomad4 SAS

AF:

0.0826

Gnomad4 FIN

AF:

0.116

Gnomad4 NFE

AF:

0.0788

Gnomad4 OTH

AF:

0.0733

Alfa

AF:

0.0736

Hom.:

1124

Bravo

AF:

0.0590

TwinsUK

AF:

0.0707

AC:

262

ALSPAC

AF:

0.0701

AC:

270

ESP6500AA

AF:

0.0134

AC:

ESP6500EA

AF:

0.0784

AC:

674

ExAC

AF:

0.0718

AC:

8718

Asia WGS

AF:

0.0630

AC:

219

AN:

3478

EpiCase

AF:

0.0738

EpiControl

AF:

0.0769

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 15450391) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Thrombophilia due to activated protein C resistance

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Congenital factor V deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Budd-Chiari syndrome

Benign:1

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. -

Factor V deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Thrombophilia due to thrombin defect

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.33

CADD

Benign

0.017

DANN

Benign

0.55

DEOGEN2

Benign

0.030

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.22

T;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Uncertain

0.26

MutationAssessor

Benign

0.14

N;.

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.22

Sift

Benign

0.65

T;T

Sift4G

Benign

0.56

T;T

Polyphen

0.0090

B;.

Vest4

0.045

MPC

0.10

ClinPred

0.011

GERP RS

-11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.051

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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