rs4220

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_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. 16/21 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

Publications

90 publications found

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 Gene-Disease associations (from GenCC):

congenital fibrinogen deficiency
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
thrombophilia
Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
congenital afibrinogenemia
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
familial dysfibrinogenemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial hypofibrinogenemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

FGB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a domain Fibrinogen C-terminal (size 256) in uniprot entity FIBB_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_005141.5

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 VariationId is 16384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
FGB	NM_005141.5 link	c.1433G>A	p.Arg478Lys	missense_variant	Exon 8 of 8	ENST00000302068.9	NP_005132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
FGB	ENST00000302068.9 link	c.1433G>A	p.Arg478Lys	missense_variant	Exon 8 of 8	1	NM_005141.5	ENSP00000306099.4
FGB	ENST00000509493.1 link	c.776G>A	p.Arg259Lys	missense_variant	Exon 6 of 6	5		ENSP00000426757.1
FGB	ENST00000502545.5 link	n.1128G>A		non_coding_transcript_exon_variant	Exon 7 of 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

GnomAD2 exomes

AF:

0.171

AC:

43021

AN:

251332

AF XY:

0.174

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 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

African (AFR)

AF:

0.0881

AC:

2948

AN:

33478

American (AMR)

AF:

0.137

AC:

6137

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.180

AC:

4710

AN:

26130

East Asian (EAS)

AF:

0.177

AC:

7008

AN:

39690

South Asian (SAS)

AF:

0.157

AC:

13568

AN:

86252

European-Finnish (FIN)

AF:

0.171

AC:

9147

AN:

53420

Middle Eastern (MID)

AF:

0.213

AC:

1230

AN:

5768

European-Non Finnish (NFE)

AF:

0.176

AC:

196184

AN:

1111718

Other (OTH)

AF:

0.175

AC:

10589

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

11701

23402

35102

46803

58504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6656

13312

19968

26624

33280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.154

AC:

23472

AN:

152048

Hom.:

2001

Cov.:

AF XY:

0.152

AC XY:

11284

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0908

AC:

3769

AN:

41496

American (AMR)

AF:

0.138

AC:

2104

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.172

AC:

594

AN:

3460

East Asian (EAS)

AF:

0.218

AC:

1125

AN:

5168

South Asian (SAS)

AF:

0.155

AC:

747

AN:

4812

European-Finnish (FIN)

AF:

0.169

AC:

1785

AN:

10564

Middle Eastern (MID)

AF:

0.205

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.187

AC:

12736

AN:

67970

Other (OTH)

AF:

0.168

AC:

353

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1004

2008

3011

4015

5019

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

268

536

804

1072

1340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.179

Hom.:

8728

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

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 20135074, 17925485, 27929198) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Congenital afibrinogenemia

Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

FIBRINOGEN BALTIMORE 2

Other:1

Oct 11, 2011

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

(source)

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;.

PhyloP100

3.3

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

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over