rs4681

Variant names:

• chr4-154569680-C-T
• rs4681
• NM_005141.5:c.1125C>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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.270
• Publications: 23 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=-0.69).
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005141.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGB	NM_005141.5	MANE Select	c.1125C>T	p.Tyr375Tyr	synonymous	Exon 7 of 8	NP_005132.2	P02675
	FGB	NM_001382763.1		c.1116C>T	p.Tyr372Tyr	synonymous	Exon 7 of 8	NP_001369692.1
	FGB	NM_001382765.1		c.1125C>T	p.Tyr375Tyr	synonymous	Exon 7 of 8	NP_001369694.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGB	ENST00000302068.9	TSL:1 MANE Select	c.1125C>T	p.Tyr375Tyr	synonymous	Exon 7 of 8	ENSP00000306099.4	P02675
	FGB	ENST00000904942.1		c.1116C>T	p.Tyr372Tyr	synonymous	Exon 7 of 8	ENSP00000575001.1
	FGB	ENST00000904940.1		c.1125C>T	p.Tyr375Tyr	synonymous	Exon 7 of 8	ENSP00000574999.1

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

GnomAD2 exomes AF: 0.168 AC: 42183 AN: 251194 AF XY: 0.172

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

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

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

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: 61 AN: 294

European-Non Finnish (NFE) AF: 0.187 AC: 12714 AN: 67960

Other (OTH) AF: 0.156 AC: 329 AN: 2114

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Congenital afibrinogenemia (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.23
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)

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