rs6056

chr4-154567669-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005141.5(FGB):c.567C>T(p.Ser189=) 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:5
• Conservation: PhyloP100: 0.0580

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 259648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-154567669-C-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
FGB	NM_005141.5	c.567C>T	p.Ser189=	synonymous_variant	4/8	ENST00000302068.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGB	ENST00000302068.9	c.567C>T	p.Ser189=	synonymous_variant	4/8	1	NM_005141.5	P1
FGB	ENST00000509493.1	c.-91C>T		5_prime_UTR_variant	2/6	5
FGB	ENST00000473984.1	n.480C>T		non_coding_transcript_exon_variant	3/3	2
FGB	ENST00000502545.5	n.548C>T		non_coding_transcript_exon_variant	4/7	5

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

GnomAD3 exomes AF: 0.172 AC: 43245 AN: 251150 Hom.: 4046 AF XY: 0.175 AC XY: 23783 AN XY: 135740

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

Gnomad4 AFR exome AF: 0.0880

Gnomad4 AMR exome AF: 0.137

Gnomad4 ASJ exome AF: 0.200

Gnomad4 EAS exome AF: 0.177

Gnomad4 SAS exome AF: 0.157

Gnomad4 FIN exome AF: 0.172

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.177

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

Gnomad4 AFR AF: 0.0907

Gnomad4 AMR AF: 0.138

Gnomad4 ASJ AF: 0.193

Gnomad4 EAS AF: 0.218

Gnomad4 SAS AF: 0.155

Gnomad4 FIN AF: 0.169

Gnomad4 NFE AF: 0.188

Gnomad4 OTH AF: 0.167

Alfa AF: 0.185 Hom.: 6641

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital afibrinogenemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	3.8
Dann	Benign	0.55

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

Other links and lift over

dbSNP: rs6056; hg19: chr4-155488821;