rs2227412

Variant names:

• chr4-154567943-A-G
• rs2227412
• NM_005141.5:c.718+123A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-154567943-A-G
• chr4-154567943-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.718+123A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 796,376 control chromosomes in the GnomAD database, including 10,663 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1970 hom., cov: 32)
  • Exomes 𝑓: 0.16 (8693 hom.)
• Consequence: FGB NM_005141.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.58
• Publications: 7 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=-0.84).
• BP6: Variant 4-154567943-A-G is Benign according to our data. Variant chr4-154567943-A-G is described in ClinVar as Benign. ClinVar VariationId is 1262054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGB	NM_005141.5	c.718+123A>G		intron_variant	Intron 4 of 7	ENST00000302068.9	NP_005132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGB	ENST00000302068.9	c.718+123A>G		intron_variant	Intron 4 of 7	1	NM_005141.5	ENSP00000306099.4
FGB	ENST00000509493.1	c.61+123A>G		intron_variant	Intron 2 of 5	5		ENSP00000426757.1
FGB	ENST00000502545.5	n.699+123A>G		intron_variant	Intron 4 of 6	5
FGB	ENST00000473984.1	n.*89A>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22592 AN: 152128 Hom.: 1960 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.0583

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.151

GnomAD4 exome AF: 0.155 AC: 100122 AN: 644130 Hom.: 8693 AF XY: 0.152 AC XY: 52609 AN XY: 347000

African (AFR) AF: 0.107 AC: 1865 AN: 17436

American (AMR) AF: 0.309 AC: 12094 AN: 39092

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 2524 AN: 20514

East Asian (EAS) AF: 0.0489 AC: 1672 AN: 34158

South Asian (SAS) AF: 0.128 AC: 8527 AN: 66512

European-Finnish (FIN) AF: 0.192 AC: 7130 AN: 37210

Middle Eastern (MID) AF: 0.124 AC: 511 AN: 4124

European-Non Finnish (NFE) AF: 0.155 AC: 60527 AN: 391244

Other (OTH) AF: 0.156 AC: 5272 AN: 33840

GnomAD4 genome AF: 0.148 AC: 22608 AN: 152246 Hom.: 1970 Cov.: 32 AF XY: 0.152 AC XY: 11308 AN XY: 74446

African (AFR) AF: 0.105 AC: 4364 AN: 41548

American (AMR) AF: 0.262 AC: 4006 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 427 AN: 3472

East Asian (EAS) AF: 0.0580 AC: 301 AN: 5188

South Asian (SAS) AF: 0.132 AC: 637 AN: 4820

European-Finnish (FIN) AF: 0.185 AC: 1960 AN: 10592

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.153 AC: 10375 AN: 68008

Other (OTH) AF: 0.158 AC: 333 AN: 2114

Alfa AF: 0.146 Hom.: 728

Bravo AF: 0.150

Asia WGS AF: 0.121 AC: 421 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 11, 2021

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	-0.84
CADD	Benign	12
DANN	Benign	0.64
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs2227412; hg19: chr4-155489095;