rs6056

Variant names:

• chr4-154567669-C-T
• rs6056
• NM_005141.5:c.567C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005141.5(FGB):​c.567C>T​(p.Ser189Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,611,650 control chromosomes in the GnomAD database, including 24,554 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2019 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22535 hom.)
• Consequence: FGB NM_005141.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0580
• Publications: 39 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 4-154567669-C-T is Benign according to our data. Variant chr4-154567669-C-T is described in ClinVar as Benign. ClinVar VariationId is 259648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.058 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	c.567C>T	p.Ser189Ser	synonymous_variant	Exon 4 of 8	ENST00000302068.9	NP_005132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGB	ENST00000302068.9	c.567C>T	p.Ser189Ser	synonymous_variant	Exon 4 of 8	1	NM_005141.5	ENSP00000306099.4

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23549 AN: 151962 Hom.: 2019 Cov.: 32

Gnomad AFR AF: 0.0905

Gnomad AMI AF: 0.222

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.170

GnomAD2 exomes AF: 0.172 AC: 43245 AN: 251150 AF XY: 0.175

Gnomad AFR exome AF: 0.0894

Gnomad AMR exome AF: 0.134

Gnomad ASJ exome AF: 0.206

Gnomad EAS exome AF: 0.230

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.187

Gnomad OTH exome AF: 0.198

GnomAD4 exome AF: 0.172 AC: 251506 AN: 1459570 Hom.: 22535 Cov.: 31 AF XY: 0.173 AC XY: 125966 AN XY: 726226

African (AFR) AF: 0.0880 AC: 2943 AN: 33460

American (AMR) AF: 0.137 AC: 6127 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 5230 AN: 26120

East Asian (EAS) AF: 0.177 AC: 7028 AN: 39676

South Asian (SAS) AF: 0.157 AC: 13547 AN: 86198

European-Finnish (FIN) AF: 0.172 AC: 9161 AN: 53416

Middle Eastern (MID) AF: 0.216 AC: 1242 AN: 5762

European-Non Finnish (NFE) AF: 0.176 AC: 195578 AN: 1109906

Other (OTH) AF: 0.177 AC: 10650 AN: 60314

GnomAD4 genome AF: 0.155 AC: 23566 AN: 152080 Hom.: 2019 Cov.: 32 AF XY: 0.152 AC XY: 11333 AN XY: 74334

African (AFR) AF: 0.0907 AC: 3762 AN: 41494

American (AMR) AF: 0.138 AC: 2103 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 669 AN: 3472

East Asian (EAS) AF: 0.218 AC: 1131 AN: 5178

South Asian (SAS) AF: 0.155 AC: 746 AN: 4816

European-Finnish (FIN) AF: 0.169 AC: 1785 AN: 10566

Middle Eastern (MID) AF: 0.209 AC: 61 AN: 292

European-Non Finnish (NFE) AF: 0.188 AC: 12755 AN: 67972

Other (OTH) AF: 0.167 AC: 352 AN: 2102

Alfa AF: 0.180 Hom.: 11916

Bravo AF: 0.154

Asia WGS AF: 0.162 AC: 563 AN: 3478

EpiCase AF: 0.183

EpiControl AF: 0.184

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 12, 2018

GeneDx

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

- -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital afibrinogenemia Benign:2

Jan 13, 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	-0.77
CADD	Benign	3.8
DANN	Benign	0.55
PhyloP100		0.058
Mutation Taster		=299/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6056; hg19: chr4-155488821;