rs2227402

Variant names:

• chr4-154565318-T-A
• rs2227402
• NM_005141.5:c.115-490T>A

Your query was ambiguous. Multiple possible variants found:

• chr4-154565318-T-A
• chr4-154565318-T-G

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.115-490T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 304,438 control chromosomes in the GnomAD database, including 4,404 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2356 hom., cov: 32)
  • Exomes 𝑓: 0.15 (2048 hom.)
• Consequence: FGB NM_005141.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.677
• Publications: 4 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=-0.82).
• BP6: Variant 4-154565318-T-A is Benign according to our data. Variant chr4-154565318-T-A is described in ClinVar as Benign. ClinVar VariationId is 1256963.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.115-490T>A		intron	N/A	NP_005132.2	P02675
	FGB	NM_001382763.1		c.115-490T>A		intron	N/A	NP_001369692.1
	FGB	NM_001382765.1		c.115-490T>A		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.115-490T>A		intron	N/A	ENSP00000306099.4	P02675
	FGB	ENST00000497097.5	TSL:1	n.122-490T>A		intron	N/A
	FGB	ENST00000904942.1		c.115-490T>A		intron	N/A	ENSP00000575001.1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25612 AN: 152006 Hom.: 2357 Cov.: 32

Gnomad AFR AF: 0.0988

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.185

GnomAD4 exome AF: 0.154 AC: 23391 AN: 152314 Hom.: 2048 Cov.: 0 AF XY: 0.152 AC XY: 13033 AN XY: 85962

African (AFR) AF: 0.0735 AC: 182 AN: 2476

American (AMR) AF: 0.109 AC: 635 AN: 5814

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 552 AN: 3654

East Asian (EAS) AF: 0.151 AC: 595 AN: 3946

South Asian (SAS) AF: 0.121 AC: 3424 AN: 28338

European-Finnish (FIN) AF: 0.168 AC: 3557 AN: 21136

Middle Eastern (MID) AF: 0.212 AC: 456 AN: 2148

European-Non Finnish (NFE) AF: 0.166 AC: 12939 AN: 77984

Other (OTH) AF: 0.154 AC: 1051 AN: 6818

GnomAD4 genome AF: 0.168 AC: 25619 AN: 152124 Hom.: 2356 Cov.: 32 AF XY: 0.166 AC XY: 12319 AN XY: 74366

African (AFR) AF: 0.0987 AC: 4096 AN: 41498

American (AMR) AF: 0.149 AC: 2274 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 713 AN: 3466

East Asian (EAS) AF: 0.219 AC: 1132 AN: 5170

South Asian (SAS) AF: 0.156 AC: 750 AN: 4820

European-Finnish (FIN) AF: 0.176 AC: 1865 AN: 10594

Middle Eastern (MID) AF: 0.243 AC: 71 AN: 292

European-Non Finnish (NFE) AF: 0.208 AC: 14131 AN: 67974

Other (OTH) AF: 0.182 AC: 385 AN: 2110

Alfa AF: 0.196 Hom.: 462

Bravo AF: 0.167

Asia WGS AF: 0.162 AC: 563 AN: 3478

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	-0.82
CADD	Benign	5.2
DANN	Benign	0.61
PhyloP100		0.68
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: rs2227402; hg19: chr4-155486470;