rs140114081

Variant names:

• chr4-154569497-TTTTG-T
• rs140114081
• NM_005141.5:c.959-13_959-10delGTTT

Your query was ambiguous. Multiple possible variants found:

• chr4-154569497-TTTTG-T
• chr4-154569497-TTTTG-TTTTGTTTG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005141.5(FGB):​c.959-13_959-10delGTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,606,216 control chromosomes in the GnomAD database, including 23,864 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1851 hom., cov: 29)
  • Exomes 𝑓: 0.17 (22013 hom.)
• Consequence: FGB NM_005141.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.53
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 4-154569497-TTTTG-T is Benign according to our data. Variant chr4-154569497-TTTTG-T is described in ClinVar as Benign. ClinVar VariationId is 259650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.206 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.959-13_959-10delGTTT		intron	N/A	NP_005132.2
	FGB	NM_001382763.1		c.950-13_950-10delGTTT		intron	N/A	NP_001369692.1
	FGB	NM_001382765.1		c.959-13_959-10delGTTT		intron	N/A	NP_001369694.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGB	ENST00000302068.9	TSL:1 MANE Select	c.959-13_959-10delGTTT		intron	N/A	ENSP00000306099.4
	FGB	ENST00000509493.1	TSL:5	c.302-13_302-10delGTTT		intron	N/A	ENSP00000426757.1
	FGB	ENST00000502545.5	TSL:5	n.939+194_939+197delGTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21525 AN: 152020 Hom.: 1852 Cov.: 29

Gnomad AFR AF: 0.0472

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.157

GnomAD2 exomes AF: 0.164 AC: 39685 AN: 241336 AF XY: 0.168

Gnomad AFR exome AF: 0.0448

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.224

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.184

Gnomad OTH exome AF: 0.191

GnomAD4 exome AF: 0.170 AC: 247039 AN: 1454078 Hom.: 22013 AF XY: 0.171 AC XY: 123651 AN XY: 723020

African (AFR) AF: 0.0425 AC: 1401 AN: 33002

American (AMR) AF: 0.130 AC: 5636 AN: 43374

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 4590 AN: 25828

East Asian (EAS) AF: 0.176 AC: 6997 AN: 39670

South Asian (SAS) AF: 0.154 AC: 12979 AN: 84156

European-Finnish (FIN) AF: 0.170 AC: 9069 AN: 53226

Middle Eastern (MID) AF: 0.208 AC: 1186 AN: 5712

European-Non Finnish (NFE) AF: 0.176 AC: 194888 AN: 1109088

Other (OTH) AF: 0.171 AC: 10293 AN: 60022

GnomAD4 genome AF: 0.142 AC: 21529 AN: 152138 Hom.: 1851 Cov.: 29 AF XY: 0.140 AC XY: 10388 AN XY: 74350

African (AFR) AF: 0.0471 AC: 1958 AN: 41550

American (AMR) AF: 0.135 AC: 2057 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 600 AN: 3472

East Asian (EAS) AF: 0.216 AC: 1116 AN: 5162

South Asian (SAS) AF: 0.155 AC: 746 AN: 4824

European-Finnish (FIN) AF: 0.167 AC: 1766 AN: 10564

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.187 AC: 12696 AN: 67958

Other (OTH) AF: 0.155 AC: 327 AN: 2114

Alfa AF: 0.179 Hom.: 514

Bravo AF: 0.139

Asia WGS AF: 0.156 AC: 541 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Congenital afibrinogenemia (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs140114081; hg19: chr4-155490649; COSMIC: COSV57418770;