rs2227403

Variant names:

• chr4-154565494-T-C
• rs2227403
• NM_005141.5:c.115-314T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005141.5(FGB):​c.115-314T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 348,362 control chromosomes in the GnomAD database, including 5,915 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2354 hom., cov: 32)
  • Exomes 𝑓: 0.18 (3561 hom.)
• Consequence: FGB NM_005141.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.245
• Publications: 2 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
• congenital afibrinogenemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• thrombophilia

  Inheritance: AR, AD Classification: STRONG Submitted by: Genomics England PanelApp
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 4-154565494-T-C is Benign according to our data. Variant chr4-154565494-T-C is described in ClinVar as Benign. ClinVar VariationId is 1241440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.208 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.115-314T>C		intron	N/A	NP_005132.2	P02675
	FGB	NM_001382763.1		c.115-314T>C		intron	N/A	NP_001369692.1
	FGB	NM_001382765.1		c.115-314T>C		intron	N/A	NP_001369694.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGB	ENST00000302068.9	TSL:1 MANE Select	c.115-314T>C		intron	N/A	ENSP00000306099.4	P02675
	FGB	ENST00000497097.5	TSL:1	n.122-314T>C		intron	N/A
	FGB	ENST00000904942.1		c.115-314T>C		intron	N/A	ENSP00000575001.1

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25626 AN: 152080 Hom.: 2355 Cov.: 32

Gnomad AFR AF: 0.0991

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.185

GnomAD4 exome AF: 0.183 AC: 35905 AN: 196162 Hom.: 3561 Cov.: 0 AF XY: 0.182 AC XY: 19025 AN XY: 104552

African (AFR) AF: 0.0981 AC: 582 AN: 5934

American (AMR) AF: 0.143 AC: 976 AN: 6802

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 1167 AN: 5622

East Asian (EAS) AF: 0.190 AC: 1798 AN: 9474

South Asian (SAS) AF: 0.148 AC: 4390 AN: 29696

European-Finnish (FIN) AF: 0.168 AC: 1735 AN: 10344

Middle Eastern (MID) AF: 0.224 AC: 176 AN: 786

European-Non Finnish (NFE) AF: 0.198 AC: 23145 AN: 116924

Other (OTH) AF: 0.183 AC: 1936 AN: 10580

GnomAD4 genome AF: 0.168 AC: 25633 AN: 152200 Hom.: 2354 Cov.: 32 AF XY: 0.166 AC XY: 12331 AN XY: 74424

African (AFR) AF: 0.0989 AC: 4111 AN: 41554

American (AMR) AF: 0.149 AC: 2274 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 715 AN: 3472

East Asian (EAS) AF: 0.219 AC: 1134 AN: 5180

South Asian (SAS) AF: 0.156 AC: 749 AN: 4812

European-Finnish (FIN) AF: 0.176 AC: 1867 AN: 10582

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.208 AC: 14125 AN: 67982

Other (OTH) AF: 0.182 AC: 385 AN: 2114

Alfa AF: 0.175 Hom.: 853

Bravo AF: 0.167

Asia WGS AF: 0.162 AC: 564 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.1
DANN	Benign	0.39
PhyloP100		-0.24
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: rs2227403; hg19: chr4-155486646;