rs4681

chr4-154569680-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.1125C>T(p.Tyr375=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.270

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=-0.69).
• BP6: Variant 4-154569680-C-T is Benign according to our data. Variant chr4-154569680-C-T is described in ClinVar as [Benign]. Clinvar id is 259645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-154569680-C-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
FGB	NM_005141.5	c.1125C>T	p.Tyr375=	synonymous_variant	7/8	ENST00000302068.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGB	ENST00000302068.9	c.1125C>T	p.Tyr375=	synonymous_variant	7/8	1	NM_005141.5	P1
FGB	ENST00000509493.1	c.468C>T	p.Tyr156=	synonymous_variant	5/6	5
FGB	ENST00000502545.5	n.939+373C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21571 AN: 151956 Hom.: 1882 Cov.: 32

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

GnomAD3 exomes AF: 0.168 AC: 42183 AN: 251194 Hom.: 3940 AF XY: 0.172 AC XY: 23303 AN XY: 135750

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 SAS exome AF: 0.153

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.: 34 AF XY: 0.172 AC XY: 125096 AN XY: 727124

Gnomad4 AFR exome AF: 0.0435

Gnomad4 AMR exome AF: 0.135

Gnomad4 ASJ exome AF: 0.180

Gnomad4 EAS exome AF: 0.177

Gnomad4 SAS exome AF: 0.157

Gnomad4 FIN exome AF: 0.171

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.173

GnomAD4 genome AF: 0.142 AC: 21575 AN: 152074 Hom.: 1881 Cov.: 32 AF XY: 0.140 AC XY: 10434 AN XY: 74314

Gnomad4 AFR AF: 0.0473

Gnomad4 AMR AF: 0.134

Gnomad4 ASJ AF: 0.173

Gnomad4 EAS AF: 0.219

Gnomad4 SAS AF: 0.155

Gnomad4 FIN AF: 0.169

Gnomad4 NFE AF: 0.187

Gnomad4 OTH AF: 0.156

Alfa AF: 0.178 Hom.: 3462

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	- -

Congenital afibrinogenemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 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	-0.69
Cadd	Benign	0.23
Dann	Benign	0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs4681; hg19: chr4-155490832; COSMIC: COSV57419287; COSMIC: COSV57419287;