rs4681

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005141.5(FGB):c.1125C>T(p.Tyr375Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,613,736 control chromosomes in the GnomAD database, including 24,166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1881 hom., cov: 32)

Exomes 𝑓: 0.17 ( 22285 hom. )

Consequence

FGB
NM_005141.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.270

Publications

23 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 4-154569680-C-T is Benign according to our data. Variant chr4-154569680-C-T is described in ClinVar as Benign. ClinVar VariationId is 259645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.27 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGB	NM_005141.5 link	c.1125C>T	p.Tyr375Tyr	synonymous_variant	Exon 7 of 8	ENST00000302068.9	NP_005132.2	P02675V9HVY1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FGB	ENST00000302068.9 link	c.1125C>T	p.Tyr375Tyr	synonymous_variant	Exon 7 of 8	1	NM_005141.5	ENSP00000306099.4	P02675
FGB	ENST00000509493.1 link	c.468C>T	p.Tyr156Tyr	synonymous_variant	Exon 5 of 6	5		ENSP00000426757.1	D6REL8
FGB	ENST00000502545.5 link	n.939+373C>T		intron_variant	Intron 6 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.142

AC:

21571

AN:

151956

Hom.:

1882

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0473

Gnomad AMI

AF:

0.221

Gnomad AMR

AF:

0.134

Gnomad ASJ

AF:

0.173

Gnomad EAS

AF:

0.218

Gnomad SAS

AF:

0.154

Gnomad FIN

AF:

0.169

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.187

Gnomad OTH

AF:

0.158

GnomAD2 exomes

AF:

0.168

AC:

42183

AN:

251194

AF XY:

0.172

show subpopulations

Gnomad AFR exome

AF:

0.0452

Gnomad AMR exome

AF:

0.133

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:

0.197

GnomAD4 exome

AF:

0.171

AC:

249744

AN:

1461662

Hom.:

22285

Cov.:

AF XY:

0.172

AC XY:

125096

AN XY:

727124

show subpopulations

African (AFR)

AF:

0.0435

AC:

1457

AN:

33474

American (AMR)

AF:

0.135

AC:

6024

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.180

AC:

4710

AN:

26136

East Asian (EAS)

AF:

0.177

AC:

7008

AN:

39694

South Asian (SAS)

AF:

0.157

AC:

13553

AN:

86256

European-Finnish (FIN)

AF:

0.171

AC:

9139

AN:

53414

Middle Eastern (MID)

AF:

0.210

AC:

1214

AN:

5768

European-Non Finnish (NFE)

AF:

0.176

AC:

196213

AN:

1111818

Other (OTH)

AF:

0.173

AC:

10426

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

11286

22572

33859

45145

56431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6634

13268

19902

26536

33170

<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:

0.142

AC:

21575

AN:

152074

Hom.:

1881

Cov.:

AF XY:

0.140

AC XY:

10434

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0473

AC:

1962

AN:

41520

American (AMR)

AF:

0.134

AC:

2053

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.173

AC:

600

AN:

3470

East Asian (EAS)

AF:

0.219

AC:

1127

AN:

5156

South Asian (SAS)

AF:

0.155

AC:

743

AN:

4808

European-Finnish (FIN)

AF:

0.169

AC:

1784

AN:

10568

Middle Eastern (MID)

AF:

0.207

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.187

AC:

12714

AN:

67960

Other (OTH)

AF:

0.156

AC:

329

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

903

1805

2708

3610

4513

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

250

500

750

1000

1250

<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:

0.169

Hom.:

4521

Bravo

AF:

0.139

Asia WGS

AF:

0.156

AC:

543

AN:

3478

EpiCase

AF:

0.183

EpiControl

AF:

0.184

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Congenital afibrinogenemia

Benign:2

Jan 12, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.23

(source)

DANN

Benign

0.16

PhyloP100

0.27

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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