rs2227421

Variant names:

• chr4-154571072-A-C
• rs2227421
• NM_005141.5:c.*422A>C

Your query was ambiguous. Multiple possible variants found:

• chr4-154571072-A-C
• chr4-154571072-A-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.*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
• Publications: 6 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=-0.73).
• BP6: Variant 4-154571072-A-C is Benign according to our data. Variant chr4-154571072-A-C is described in ClinVar as Benign. ClinVar VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGB	NM_005141.5	MANE Select	c.*422A>C		3_prime_UTR	Exon 8 of 8	NP_005132.2
	FGB	NM_001382763.1		c.*422A>C		3_prime_UTR	Exon 8 of 8	NP_001369692.1
	FGB	NM_001382765.1		c.*422A>C		3_prime_UTR	Exon 8 of 8	NP_001369694.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGB	ENST00000302068.9	TSL:1 MANE Select	c.*422A>C		3_prime_UTR	Exon 8 of 8	ENSP00000306099.4

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

African (AFR) AF: 0.136 AC: 331 AN: 2434

American (AMR) AF: 0.206 AC: 882 AN: 4286

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 945 AN: 2912

East Asian (EAS) AF: 0.129 AC: 600 AN: 4652

South Asian (SAS) AF: 0.302 AC: 6467 AN: 21386

European-Finnish (FIN) AF: 0.233 AC: 1368 AN: 5860

Middle Eastern (MID) AF: 0.330 AC: 149 AN: 452

European-Non Finnish (NFE) AF: 0.335 AC: 25027 AN: 74708

Other (OTH) AF: 0.304 AC: 1856 AN: 6114

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

African (AFR) AF: 0.147 AC: 6115 AN: 41476

American (AMR) AF: 0.224 AC: 3422 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 1207 AN: 3468

East Asian (EAS) AF: 0.141 AC: 729 AN: 5172

South Asian (SAS) AF: 0.310 AC: 1491 AN: 4804

European-Finnish (FIN) AF: 0.244 AC: 2574 AN: 10566

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.334 AC: 22704 AN: 67976

Other (OTH) AF: 0.285 AC: 602 AN: 2110

Alfa AF: 0.311 Hom.: 23868

Bravo AF: 0.249

Asia WGS AF: 0.252 AC: 876 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital afibrinogenemia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.5
DANN	Benign	0.84
PhyloP100		-0.018
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: rs2227421; hg19: chr4-155492224;