rs1046712

Positions:

chr1-169541237-G-T

Variant summary

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

The NM_000130.5(F5):c.3853C>A(p.Leu1285Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,603,754 control chromosomes in the GnomAD database, including 24,165 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 1350 hom., cov: 26)

Exomes 𝑓: 0.17 ( 22815 hom. )

Consequence

F5
NM_000130.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:9

Conservation

PhyloP100: -0.143

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=0.0068129003).

BP6

Variant 1-169541237-G-T is Benign according to our data. Variant chr1-169541237-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 255205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169541237-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.174 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.3853C>A	p.Leu1285Ile	missense_variant	13/25	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.3853C>A	p.Leu1285Ile	missense_variant	13/25	1	NM_000130.5	ENSP00000356771.3		P12259
F5	ENST00000367796.3 linkuse as main transcript	c.3868C>A	p.Leu1290Ile	missense_variant	13/25	5		ENSP00000356770.3		A0A0A0MRJ7

Frequencies

GnomAD3 genomes

AF:

0.162

AC:

23833

AN:

147284

Hom.:

1353

Cov.:

show subpopulations

Gnomad AFR

AF:

0.157

Gnomad AMI

AF:

0.122

Gnomad AMR

AF:

0.145

Gnomad ASJ

AF:

0.225

Gnomad EAS

AF:

0.0917

Gnomad SAS

AF:

0.184

Gnomad FIN

AF:

0.192

Gnomad MID

AF:

0.172

Gnomad NFE

AF:

0.165

Gnomad OTH

AF:

0.163

GnomAD3 exomes

AF:

0.174

AC:

43421

AN:

249792

Hom.:

3963

AF XY:

0.177

AC XY:

23922

AN XY:

135034

show subpopulations

Gnomad AFR exome

AF:

0.169

Gnomad AMR exome

AF:

0.132

Gnomad ASJ exome

AF:

0.252

Gnomad EAS exome

AF:

0.0957

Gnomad SAS exome

AF:

0.201

Gnomad FIN exome

AF:

0.204

Gnomad NFE exome

AF:

0.180

Gnomad OTH exome

AF:

0.172

GnomAD4 exome

AF:

0.174

AC:

253871

AN:

1456364

Hom.:

22815

Cov.:

129

AF XY:

0.175

AC XY:

127054

AN XY:

724344

show subpopulations

Gnomad4 AFR exome

AF:

0.173

Gnomad4 AMR exome

AF:

0.137

Gnomad4 ASJ exome

AF:

0.251

Gnomad4 EAS exome

AF:

0.0892

Gnomad4 SAS exome

AF:

0.199

Gnomad4 FIN exome

AF:

0.204

Gnomad4 NFE exome

AF:

0.174

Gnomad4 OTH exome

AF:

0.176

GnomAD4 genome

AF:

0.162

AC:

23841

AN:

147390

Hom.:

1350

Cov.:

AF XY:

0.162

AC XY:

11665

AN XY:

71960

show subpopulations

Gnomad4 AFR

AF:

0.157

Gnomad4 AMR

AF:

0.145

Gnomad4 ASJ

AF:

0.225

Gnomad4 EAS

AF:

0.0915

Gnomad4 SAS

AF:

0.184

Gnomad4 FIN

AF:

0.192

Gnomad4 NFE

AF:

0.165

Gnomad4 OTH

AF:

0.162

Alfa

AF:

0.178

Hom.:

1466

TwinsUK

AF:

0.183

AC:

677

ALSPAC

AF:

0.173

AC:

667

ESP6500AA

AF:

0.176

AC:

775

ESP6500EA

AF:

0.175

AC:

1502

ExAC

AF:

0.179

AC:

21699

Asia WGS

AF:

0.154

AC:

535

AN:

3462

EpiCase

AF:

0.183

EpiControl

AF:

0.183

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 25.185% in gnomAD_ExomesFounderPop) based on the frequency threshold of 5.0% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease. -
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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Factor V deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Thrombophilia due to thrombin defect

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.20

DANN

Benign

0.16

DEOGEN2

Benign

0.028

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.099

LIST_S2

Benign

0.55

T;T

MetaRNN

Benign

0.0068

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Benign

0.17

PROVEAN

Benign

-0.29

N;N

REVEL

Benign

0.031

Sift

Benign

0.15

T;T

Sift4G

Benign

0.29

T;T

Polyphen

0.0030

B;.

Vest4

0.083

MPC

0.22

ClinPred

0.0053

GERP RS

-1.4

Varity_R

0.024

gMVP

0.19

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