rs4220

Variant names:

• chr4-154570607-G-A
• rs4220
• NM_005141.5:c.1433G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_005141.5(FGB):​c.1433G>A​(p.Arg478Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,613,606 control chromosomes in the GnomAD database, including 24,434 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2001 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22433 hom.)
• Consequence: FGB NM_005141.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 3.26
• Publications: 90 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 -18 ACMG points.

• PM1: In a domain Fibrinogen C-terminal (size 256) in uniprot entity FIBB_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_005141.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0014242828).
• BP6: Variant 4-154570607-G-A is Benign according to our data. Variant chr4-154570607-G-A is described in ClinVar as Benign. ClinVar VariationId is 16384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.207 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.1433G>A	p.Arg478Lys	missense	Exon 8 of 8	NP_005132.2	P02675
	FGB	NM_001382763.1		c.1424G>A	p.Arg475Lys	missense	Exon 8 of 8	NP_001369692.1
	FGB	NM_001382765.1		c.1409G>A	p.Arg470Lys	missense	Exon 8 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.1433G>A	p.Arg478Lys	missense	Exon 8 of 8	ENSP00000306099.4	P02675
	FGB	ENST00000904942.1		c.1424G>A	p.Arg475Lys	missense	Exon 8 of 8	ENSP00000575001.1
	FGB	ENST00000904940.1		c.1409G>A	p.Arg470Lys	missense	Exon 8 of 8	ENSP00000574999.1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23455 AN: 151930 Hom.: 2001 Cov.: 32

Gnomad AFR AF: 0.0907

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.170

GnomAD2 exomes AF: 0.171 AC: 43021 AN: 251332 AF XY: 0.174

Gnomad AFR exome AF: 0.0896

Gnomad AMR exome AF: 0.135

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: 0.198

GnomAD4 exome AF: 0.172 AC: 251521 AN: 1461558 Hom.: 22433 Cov.: 32 AF XY: 0.173 AC XY: 125915 AN XY: 727090

African (AFR) AF: 0.0881 AC: 2948 AN: 33478

American (AMR) AF: 0.137 AC: 6137 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4710 AN: 26130

East Asian (EAS) AF: 0.177 AC: 7008 AN: 39690

South Asian (SAS) AF: 0.157 AC: 13568 AN: 86252

European-Finnish (FIN) AF: 0.171 AC: 9147 AN: 53420

Middle Eastern (MID) AF: 0.213 AC: 1230 AN: 5768

European-Non Finnish (NFE) AF: 0.176 AC: 196184 AN: 1111718

Other (OTH) AF: 0.175 AC: 10589 AN: 60386

GnomAD4 genome AF: 0.154 AC: 23472 AN: 152048 Hom.: 2001 Cov.: 32 AF XY: 0.152 AC XY: 11284 AN XY: 74336

African (AFR) AF: 0.0908 AC: 3769 AN: 41496

American (AMR) AF: 0.138 AC: 2104 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 594 AN: 3460

East Asian (EAS) AF: 0.218 AC: 1125 AN: 5168

South Asian (SAS) AF: 0.155 AC: 747 AN: 4812

European-Finnish (FIN) AF: 0.169 AC: 1785 AN: 10564

Middle Eastern (MID) AF: 0.205 AC: 60 AN: 292

European-Non Finnish (NFE) AF: 0.187 AC: 12736 AN: 67970

Other (OTH) AF: 0.168 AC: 353 AN: 2106

Alfa AF: 0.179 Hom.: 8728

Bravo AF: 0.153

TwinsUK AF: 0.164 AC: 607

ALSPAC AF: 0.173 AC: 665

ESP6500AA AF: 0.0885 AC: 390

ESP6500EA AF: 0.190 AC: 1633

ExAC AF: 0.173 AC: 21021

Asia WGS AF: 0.161 AC: 562 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)
-	-	-	FIBRINOGEN BALTIMORE 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	6.7
DANN	Benign	0.56
DEOGEN2	Benign	0.059	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	N
PhyloP100		3.3
PrimateAI	Benign	0.45	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.22
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.058
MPC		0.17
ClinPred		0.0047	T
GERP RS		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.15
gMVP		0.69
Mutation Taster		=99/1	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: rs4220; hg19: chr4-155491759; COSMIC: COSV57417810; COSMIC: COSV57417810;