rs6054

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_005141.5(FGB):c.794C>T(p.Pro265Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00425 in 1,597,176 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0028 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0044 ( 20 hom. )

Consequence

FGB
NM_005141.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:9B:3

Conservation

PhyloP100: 5.90

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.045531124).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00276 (419/152052) while in subpopulation NFE AF= 0.00512 (348/67988). AF 95% confidence interval is 0.00468. There are 0 homozygotes in gnomad4. There are 163 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 20 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGB	NM_005141.5 link	c.794C>T	p.Pro265Leu	missense_variant	Exon 5 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.794C>T	p.Pro265Leu	missense_variant	Exon 5 of 8	1	NM_005141.5	ENSP00000306099.4	P02675
FGB	ENST00000509493.1 link	c.137C>T	p.Pro46Leu	missense_variant	Exon 3 of 6	5		ENSP00000426757.1	D6REL8
FGB	ENST00000502545.5 link	n.775C>T		non_coding_transcript_exon_variant	Exon 5 of 7	5

Frequencies

GnomAD3 genomes

AF:

0.00276

AC:

419

AN:

151936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0000946

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00512

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00235

AC:

591

AN:

251290

Hom.:

AF XY:

0.00242

AC XY:

328

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000598

Gnomad SAS exome

AF:

0.00111

Gnomad FIN exome

AF:

0.000278

Gnomad NFE exome

AF:

0.00443

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00441

AC:

6373

AN:

1445124

Hom.:

Cov.:

AF XY:

0.00426

AC XY:

3067

AN XY:

720022

show subpopulations

Gnomad4 AFR exome

AF:

0.000512

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.000858

Gnomad4 SAS exome

AF:

0.000896

Gnomad4 FIN exome

AF:

0.000319

Gnomad4 NFE exome

AF:

0.00547

Gnomad4 OTH exome

AF:

0.00327

GnomAD4 genome

AF:

0.00276

AC:

419

AN:

152052

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0000946

Gnomad4 NFE

AF:

0.00512

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00387

Hom.:

Bravo

AF:

0.00248

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.00243

AC:

295

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00420

EpiControl

AF:

0.00421

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:9Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Congenital afibrinogenemia

Pathogenic:1Benign:1

Jun 01, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Uncertain:1Benign:1

Jan 20, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FGB c.794C>T (p.Pro265Leu) results in a non-conservative amino acid change located in the C-terminal globular domain (IPR002181) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0024 in 251290 control chromosomes, predominantly at a frequency of 0.0044 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in FGB causing Afibrinogenemia, Congenital phenotype. c.794C>T has been reported in several heterozygous individuals affected with hypofibrinogenemia and various (suspected) bleeding/coagulation disorders (Brennan_2000, Morris_2009, Downes_2019, Almazni_2020, Preisler_2020). Large scale population studies demonstrated an association with slightly lower (~10%) fibrinogen levels (Wassel_2010, Huffman_2015, de Vries_2016). In addition, at least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated decreased clot formation and clot lysis in heterozygous patient samples, which corresponded to about 70% of the control values (Morris_2009). The following publications have been ascertained in the context of this evaluation (PMID: 31064749, 32935436, 10688828, 33477601, 26105150, 19420351, 20978265, 26561523). ClinVar contains an entry for this variant (Variation ID: 517313). Based on the evidence outlined above, the variant was classified as likely benign. -

Mar 28, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Pro265Leu (NM _005141.4 c.794C>T) variant in FGB has been reported in 3 compound heterozygous and 1 homozygous individuals with Hypofibrinogenemia or Chronic thromboembolic p ulmonary hypertension (CTEPH), though the additional variants found in heterozyg osity were not well-established pathogenic variants (Brennan 2000 and Morris 200 9). In vitro functional studies provide conflicting data (Brennan 2000 and Morri s 2009). This variant has been identified in 0.381% (254/66716) of European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs52828882, rs2227436, rs6054) as well as 5% of controls in the Brennan 2000 study. In summary, the clinical significance of the p.Pro265Leu variant is uncertain; however, based on population frequency and functional data we favor a benign interpretation. -

Abnormal bleeding

Pathogenic:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Thrombus

Uncertain:1

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FGB-related disorder

Uncertain:1

Jun 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FGB c.794C>T variant is predicted to result in the amino acid substitution p.Pro265Leu. This variant, also described using legacy nomenclature as p.Pro235Leu, has been reported in individuals with hypofibrinogenemia, chronic thromboembolic pulmonary hypertension, or platelet defect (Brennan et al. 2000. PubMed ID: 10688828; Morris et al. 2009. PubMed ID: 19420351; Almazni et al. 2020. PubMed ID: 32935436). However, this variant has also been reported in healthy controls (Brennan et al. 2000. PubMed ID: 10688828). This variant is reported in 0.44% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant has conflicting interpretations of likely benign, uncertain significance, likely pathogenic, and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/517313/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Thrombocytopenia;C1458140:Abnormal bleeding

Uncertain:1

May 01, 2020

Birmingham Platelet Group; University of Birmingham

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Hypofibrinogenemia

Uncertain:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Afibrinogenemia

Uncertain:1

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial dysfibrinogenemia

Uncertain:1

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.046

T;T

MetaSVM

Uncertain

0.50

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.6

D;D

REVEL

Uncertain

0.57

Sift

Uncertain

0.011

D;T

Sift4G

Benign

0.099

T;T

Polyphen

1.0

D;.

Vest4

0.82

MVP

0.97

MPC

0.70

ClinPred

0.058

GERP RS

5.8

Varity_R

0.58

gMVP

0.86

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