4-154571269-T-C

Variant names:

• chr4-154571269-T-C
• rs2227439
• NM_005141.5:c.*619T>C

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.*619T>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 0.91 in 151,990 control chromosomes in the GnomAD database, including 63,088 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.91 (63088 hom., cov: 29)
• Consequence: FGB NM_005141.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.38
• Publications: 5 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=-1.04).
• BP6: Variant 4-154571269-T-C is Benign according to our data. Variant chr4-154571269-T-C is described in ClinVar as Benign. ClinVar VariationId is 347787.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGB	NM_005141.5	c.*619T>C		3_prime_UTR_variant	Exon 8 of 8	ENST00000302068.9	NP_005132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGB	ENST00000302068.9	c.*619T>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_005141.5	ENSP00000306099.4

Frequencies

GnomAD3 genomes AF: 0.910 AC: 138144 AN: 151872 Hom.: 63040 Cov.: 29

Gnomad AFR AF: 0.979

Gnomad AMI AF: 0.882

Gnomad AMR AF: 0.896

Gnomad ASJ AF: 0.830

Gnomad EAS AF: 0.964

Gnomad SAS AF: 0.873

Gnomad FIN AF: 0.859

Gnomad MID AF: 0.921

Gnomad NFE AF: 0.881

Gnomad OTH AF: 0.912

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

GnomAD4 genome AF: 0.910 AC: 138249 AN: 151990 Hom.: 63088 Cov.: 29 AF XY: 0.907 AC XY: 67369 AN XY: 74260

African (AFR) AF: 0.979 AC: 40575 AN: 41458

American (AMR) AF: 0.895 AC: 13667 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.830 AC: 2879 AN: 3468

East Asian (EAS) AF: 0.964 AC: 4976 AN: 5162

South Asian (SAS) AF: 0.873 AC: 4183 AN: 4794

European-Finnish (FIN) AF: 0.859 AC: 9072 AN: 10560

Middle Eastern (MID) AF: 0.918 AC: 270 AN: 294

European-Non Finnish (NFE) AF: 0.881 AC: 59905 AN: 67976

Other (OTH) AF: 0.911 AC: 1919 AN: 2106

Alfa AF: 0.889 Hom.: 7023

Bravo AF: 0.917

Asia WGS AF: 0.925 AC: 3213 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital afibrinogenemia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-1.0
CADD	Benign	0.76
DANN	Benign	0.23
PhyloP100		-2.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2227439; hg19: chr4-155492421;