rs2227421

Positions:

• chr4-154571072-A-C
• chr4-154571072-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005141.5(FGB):​c.*422A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 274,844 control chromosomes in the GnomAD database, including 11,547 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5620 hom., cov: 32)
  • Exomes 𝑓: 0.31 (5927 hom.)
• Consequence: FGB NM_005141.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0180

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 4-154571072-A-C is Benign according to our data. Variant chr4-154571072-A-C is described in ClinVar as [Benign]. Clinvar id is 347782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGB	NM_005141.5	c.*422A>C		3_prime_UTR_variant	8/8	ENST00000302068.9	NP_005132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGB	ENST00000302068.9	c.*422A>C		3_prime_UTR_variant	8/8	1	NM_005141.5	ENSP00000306099	P1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39105 AN: 151922 Hom.: 5621 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.289

GnomAD4 exome AF: 0.306 AC: 37625 AN: 122804 Hom.: 5927 Cov.: 0 AF XY: 0.305 AC XY: 20181 AN XY: 66162

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.206

Gnomad4 ASJ exome AF: 0.325

Gnomad4 EAS exome AF: 0.129

Gnomad4 SAS exome AF: 0.302

Gnomad4 FIN exome AF: 0.233

Gnomad4 NFE exome AF: 0.335

Gnomad4 OTH exome AF: 0.304

GnomAD4 genome AF: 0.257 AC: 39097 AN: 152040 Hom.: 5620 Cov.: 32 AF XY: 0.253 AC XY: 18785 AN XY: 74318

Gnomad4 AFR AF: 0.147

Gnomad4 AMR AF: 0.224

Gnomad4 ASJ AF: 0.348

Gnomad4 EAS AF: 0.141

Gnomad4 SAS AF: 0.310

Gnomad4 FIN AF: 0.244

Gnomad4 NFE AF: 0.334

Gnomad4 OTH AF: 0.285

Alfa AF: 0.323 Hom.: 9253

Bravo AF: 0.249

Asia WGS AF: 0.252 AC: 876 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Congenital afibrinogenemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.5
DANN	Benign	0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs2227421; hg19: chr4-155492224;