rs2227401

Variant names:

• chr4-154565229-C-T
• rs2227401
• NM_005141.5:c.115-579C>T

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.115-579C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 461,956 control chromosomes in the GnomAD database, including 8,096 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2350 hom., cov: 32)
  • Exomes 𝑓: 0.18 (5746 hom.)
• Consequence: FGB NM_005141.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.148
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 4-154565229-C-T is Benign according to our data. Variant chr4-154565229-C-T is described in ClinVar as [Benign]. Clinvar id is 1234634.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGB	NM_005141.5	c.115-579C>T		intron_variant	Intron 1 of 7	ENST00000302068.9	NP_005132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGB	ENST00000302068.9	c.115-579C>T		intron_variant	Intron 1 of 7	1	NM_005141.5	ENSP00000306099.4

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25591 AN: 152044 Hom.: 2351 Cov.: 32

Gnomad AFR AF: 0.0988

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.218

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

GnomAD2 exomes AF: 0.175 AC: 24303 AN: 139070 AF XY: 0.178

Gnomad AFR exome AF: 0.0871

Gnomad AMR exome AF: 0.135

Gnomad ASJ exome AF: 0.209

Gnomad EAS exome AF: 0.219

Gnomad FIN exome AF: 0.172

Gnomad NFE exome AF: 0.197

Gnomad OTH exome AF: 0.213

GnomAD4 exome AF: 0.184 AC: 57132 AN: 309792 Hom.: 5746 Cov.: 0 AF XY: 0.186 AC XY: 32596 AN XY: 175528

African (AFR) AF: 0.0928 AC: 757 AN: 8160

American (AMR) AF: 0.137 AC: 3561 AN: 25904

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 2192 AN: 10562

East Asian (EAS) AF: 0.205 AC: 1766 AN: 8608

South Asian (SAS) AF: 0.154 AC: 8967 AN: 58060

European-Finnish (FIN) AF: 0.178 AC: 4776 AN: 26866

Middle Eastern (MID) AF: 0.234 AC: 646 AN: 2756

European-Non Finnish (NFE) AF: 0.205 AC: 31800 AN: 154984

Other (OTH) AF: 0.192 AC: 2667 AN: 13892

GnomAD4 genome AF: 0.168 AC: 25598 AN: 152164 Hom.: 2350 Cov.: 32 AF XY: 0.165 AC XY: 12314 AN XY: 74410

African (AFR) AF: 0.0987 AC: 4097 AN: 41528

American (AMR) AF: 0.148 AC: 2270 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 714 AN: 3468

East Asian (EAS) AF: 0.219 AC: 1131 AN: 5172

South Asian (SAS) AF: 0.156 AC: 751 AN: 4824

European-Finnish (FIN) AF: 0.176 AC: 1857 AN: 10578

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

European-Non Finnish (NFE) AF: 0.208 AC: 14123 AN: 67988

Other (OTH) AF: 0.182 AC: 384 AN: 2114

Alfa AF: 0.195 Hom.: 3559

Bravo AF: 0.167

Asia WGS AF: 0.163 AC: 565 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.6
DANN	Benign	0.58
PhyloP100		-0.15
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: rs2227401; hg19: chr4-155486381;