rs4220

Positions:

chr4-154570607-G-A

Variant summary

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

The NM_005141.5(FGB):c.1433G>A(p.Arg478Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,613,606 control chromosomes in the GnomAD database, including 24,434 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 Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2001 hom., cov: 32)

Exomes 𝑓: 0.17 ( 22433 hom. )

Consequence

FGB
NM_005141.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 3.26

Variant links:

Genes affected

FGB (HGNC:3662): (fibrinogen beta chain) The protein encoded by this gene is the beta component of fibrinogen, a blood-borne glycoprotein comprised of three pairs of nonidentical polypeptide chains. Following vascular injury, fibrinogen is cleaved by thrombin to form fibrin which is the most abundant component of blood clots. In addition, various cleavage products of fibrinogen and fibrin regulate cell adhesion and spreading, display vasoconstrictor and chemotactic activities, and are mitogens for several cell types. Fibrinogen serves key roles in hemostasis and antimicrobial host defense. Mutations in this gene lead to several disorders, including afibrinogenemia, dysfibrinogenemia, hypodysfibrinogenemia and thrombotic tendency. [provided by RefSeq, Aug 2020]

FGB links:

FGB (HGNC:):

FGB 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=0.0014242828).

BP6

Variant 4-154570607-G-A is Benign according to our data. Variant chr4-154570607-G-A is described in ClinVar as [Benign]. Clinvar id is 16384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-154570607-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGB	NM_005141.5 linkuse as main transcript	c.1433G>A	p.Arg478Lys	missense_variant	8/8	ENST00000302068.9	NP_005132.2	P02675V9HVY1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FGB	ENST00000302068.9 linkuse as main transcript	c.1433G>A	p.Arg478Lys	missense_variant	8/8	1	NM_005141.5	ENSP00000306099.4	P02675
FGB	ENST00000509493.1 linkuse as main transcript	c.776G>A	p.Arg259Lys	missense_variant	6/6	5		ENSP00000426757.1	D6REL8
FGB	ENST00000502545.5 linkuse as main transcript	n.1128G>A		non_coding_transcript_exon_variant	7/7	5

Frequencies

GnomAD3 genomes

AF:

0.154

AC:

23455

AN:

151930

Hom.:

2001

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0907

Gnomad AMI

AF:

0.220

Gnomad AMR

AF:

0.138

Gnomad ASJ

AF:

0.172

Gnomad EAS

AF:

0.217

Gnomad SAS

AF:

0.155

Gnomad FIN

AF:

0.169

Gnomad MID

AF:

0.201

Gnomad NFE

AF:

0.187

Gnomad OTH

AF:

0.170

GnomAD3 exomes

AF:

0.171

AC:

43021

AN:

251332

Hom.:

4003

AF XY:

0.174

AC XY:

23653

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.0896

Gnomad AMR exome

AF:

0.135

Gnomad ASJ exome

AF:

0.185

Gnomad EAS exome

AF:

0.229

Gnomad SAS exome

AF:

0.154

Gnomad FIN exome

AF:

0.168

Gnomad NFE exome

AF:

0.187

Gnomad OTH exome

AF:

0.198

GnomAD4 exome

AF:

0.172

AC:

251521

AN:

1461558

Hom.:

22433

Cov.:

AF XY:

0.173

AC XY:

125915

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.0881

Gnomad4 AMR exome

AF:

0.137

Gnomad4 ASJ exome

AF:

0.180

Gnomad4 EAS exome

AF:

0.177

Gnomad4 SAS exome

AF:

0.157

Gnomad4 FIN exome

AF:

0.171

Gnomad4 NFE exome

AF:

0.176

Gnomad4 OTH exome

AF:

0.175

GnomAD4 genome

AF:

0.154

AC:

23472

AN:

152048

Hom.:

2001

Cov.:

AF XY:

0.152

AC XY:

11284

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0908

Gnomad4 AMR

AF:

0.138

Gnomad4 ASJ

AF:

0.172

Gnomad4 EAS

AF:

0.218

Gnomad4 SAS

AF:

0.155

Gnomad4 FIN

AF:

0.169

Gnomad4 NFE

AF:

0.187

Gnomad4 OTH

AF:

0.168

Alfa

AF:

0.184

Hom.:

6553

Bravo

AF:

0.153

TwinsUK

AF:

0.164

AC:

607

ALSPAC

AF:

0.173

AC:

665

ESP6500AA

AF:

0.0885

AC:

390

ESP6500EA

AF:

0.190

AC:

1633

ExAC

AF:

0.173

AC:

21021

Asia WGS

AF:

0.161

AC:

562

AN:

3478

EpiCase

AF:

0.183

EpiControl

AF:

0.184

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 20135074, 17925485, 27929198) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Congenital afibrinogenemia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

FIBRINOGEN BALTIMORE 2

Other:1

other, no assertion criteria provided

literature only

OMIM

Oct 11, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

6.7

DANN

Benign

0.56

DEOGEN2

Benign

0.059

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.44

T;T

MetaRNN

Benign

0.0014

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.4

N;.

PrimateAI

Benign

0.45

PROVEAN

Benign

1.4

N;N

REVEL

Benign

0.22

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.058

MPC

0.17

ClinPred

0.0047

GERP RS

-3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.15

gMVP

0.69

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