rs2227395

Variant names:

• chr4-154563359-G-A
• rs2227395
• NM_005141.5:c.114+227G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005141.5(FGB):​c.114+227G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 151,702 control chromosomes in the GnomAD database, including 2,343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.17 (2343 hom., cov: 32)
• Consequence: FGB NM_005141.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.04
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 4-154563359-G-A is Benign according to our data. Variant chr4-154563359-G-A is described in ClinVar as Benign. ClinVar VariationId is 1285883.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGB	NM_005141.5	MANE Select	c.114+227G>A		intron	N/A	NP_005132.2
	FGB	NM_001382763.1		c.114+227G>A		intron	N/A	NP_001369692.1
	FGB	NM_001382765.1		c.114+227G>A		intron	N/A	NP_001369694.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGB	ENST00000302068.9	TSL:1 MANE Select	c.114+227G>A		intron	N/A	ENSP00000306099.4
	FGB	ENST00000497097.5	TSL:1	n.121+227G>A		intron	N/A
	FGB	ENST00000509493.1	TSL:5	c.-168+227G>A		intron	N/A	ENSP00000426757.1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25512 AN: 151588 Hom.: 2344 Cov.: 32

Gnomad AFR AF: 0.0989

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.184

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.168 AC: 25518 AN: 151702 Hom.: 2343 Cov.: 32 AF XY: 0.165 AC XY: 12259 AN XY: 74146

African (AFR) AF: 0.0987 AC: 4094 AN: 41464

American (AMR) AF: 0.148 AC: 2261 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 712 AN: 3464

East Asian (EAS) AF: 0.217 AC: 1126 AN: 5182

South Asian (SAS) AF: 0.156 AC: 752 AN: 4816

European-Finnish (FIN) AF: 0.176 AC: 1849 AN: 10526

Middle Eastern (MID) AF: 0.236 AC: 69 AN: 292

European-Non Finnish (NFE) AF: 0.208 AC: 14073 AN: 67710

Other (OTH) AF: 0.181 AC: 380 AN: 2094

Alfa AF: 0.165 Hom.: 599

Bravo AF: 0.167

Asia WGS AF: 0.162 AC: 558 AN: 3456

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.3
DANN	Benign	0.17
PhyloP100		-1.0
PromoterAI		0.021	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2227395; hg19: chr4-155484511;