rs6054

Variant names:

• chr4-154568456-C-T
• rs6054
• NM_005141.5:c.794C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-154568456-C-T
• chr4-154568456-C-A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM1 BP4_Strong BS1 BS2

The NM_005141.5(FGB):​c.794C>T​(p.Pro265Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00425 in 1,597,176 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0044 (20 hom.)
• Consequence: FGB NM_005141.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:11 B:2
• Conservation: PhyloP100: 5.90
• Publications: 27 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 -10 ACMG points.

• PM1: In a domain Fibrinogen C-terminal (size 256) in uniprot entity FIBB_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_005141.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.045531124).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00276 (419/152052) while in subpopulation NFE AF = 0.00512 (348/67988). AF 95% confidence interval is 0.00468. There are 0 homozygotes in GnomAd4. There are 163 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 20 AD,AR,SD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGB	NM_005141.5	MANE Select	c.794C>T	p.Pro265Leu	missense	Exon 5 of 8	NP_005132.2	P02675
	FGB	NM_001382763.1		c.794C>T	p.Pro265Leu	missense	Exon 5 of 8	NP_001369692.1
	FGB	NM_001382765.1		c.794C>T	p.Pro265Leu	missense	Exon 5 of 8	NP_001369694.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGB	ENST00000302068.9	TSL:1 MANE Select	c.794C>T	p.Pro265Leu	missense	Exon 5 of 8	ENSP00000306099.4	P02675
	FGB	ENST00000904942.1		c.794C>T	p.Pro265Leu	missense	Exon 5 of 8	ENSP00000575001.1
	FGB	ENST00000904940.1		c.794C>T	p.Pro265Leu	missense	Exon 5 of 8	ENSP00000574999.1

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 419 AN: 151936 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00512

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00235 AC: 591 AN: 251290 AF XY: 0.00242

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00443

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00441 AC: 6373 AN: 1445124 Hom.: 20 Cov.: 27 AF XY: 0.00426 AC XY: 3067 AN XY: 720022

African (AFR) AF: 0.000512 AC: 17 AN: 33190

American (AMR) AF: 0.000514 AC: 23 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26036

East Asian (EAS) AF: 0.000858 AC: 34 AN: 39614

South Asian (SAS) AF: 0.000896 AC: 77 AN: 85904

European-Finnish (FIN) AF: 0.000319 AC: 17 AN: 53338

Middle Eastern (MID) AF: 0.000873 AC: 5 AN: 5726

European-Non Finnish (NFE) AF: 0.00547 AC: 6003 AN: 1096726

Other (OTH) AF: 0.00327 AC: 196 AN: 59884

GnomAD4 genome AF: 0.00276 AC: 419 AN: 152052 Hom.: 0 Cov.: 31 AF XY: 0.00219 AC XY: 163 AN XY: 74310

African (AFR) AF: 0.00113 AC: 47 AN: 41470

American (AMR) AF: 0.000655 AC: 10 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5178

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4806

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00512 AC: 348 AN: 67988

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00392 Hom.: 8

Bravo AF: 0.00248

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00243 AC: 295

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00420

EpiControl AF: 0.00421

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	1	1	not specified (2)
1	-	-	Abnormal bleeding (1)
-	1	-	Afibrinogenemia (1)
-	1	-	Congenital afibrinogenemia (1)
-	1	-	Familial dysfibrinogenemia (1)
-	1	-	FGB-related disorder (1)
-	1	-	Hypofibrinogenemia (1)
-	1	-	Thrombocytopenia;C1458140:Abnormal bleeding (1)
-	1	-	Thrombus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.046	T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.011	D
Sift4G	Benign	0.099	T
Polyphen		1.0	D
Vest4		0.82
MVP		0.97
MPC		0.70
ClinPred		0.058	T
GERP RS		5.8
Varity_R		0.58
gMVP		0.86
Mutation Taster		=9/91	disease causing (ClinVar)

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: rs6054; hg19: chr4-155489608;