rs6063

Positions:

chr4-154609725-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP4_StrongBP6BS2

The NM_021870.3(FGG):c.571G>A(p.Gly191Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00387 in 1,613,896 control chromosomes in the GnomAD database, including 21 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 0.0033 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 19 hom. )

Consequence

FGG
NM_021870.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:4

Conservation

PhyloP100: 7.62

Variant links:

Genes affected

FGG (HGNC:3694): (fibrinogen gamma chain) The protein encoded by this gene is the gamma 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. Mutations in this gene lead to several disorders, including dysfibrinogenemia, hypofibrinogenemia and thrombophilia. Alternative splicing results in transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

FGG links:

FGG (HGNC:):

FGG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, REVEL [when max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.0155365765).

BP6

Variant 4-154609725-C-T is Benign according to our data. Variant chr4-154609725-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16378.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3, Benign=1}.

BS2

High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGG	NM_021870.3 linkuse as main transcript	c.571G>A	p.Gly191Arg	missense_variant	6/9	ENST00000336098.8	NP_068656.2	P02679-1
FGG	NM_000509.6 linkuse as main transcript	c.571G>A	p.Gly191Arg	missense_variant	6/10		NP_000500.2	P02679-2A0A140VJJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGG	ENST00000336098.8 linkuse as main transcript	c.571G>A	p.Gly191Arg	missense_variant	6/9	2	NM_021870.3	ENSP00000336829.3		P02679-1

Frequencies

GnomAD3 genomes

AF:

0.00335

AC:

509

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000990

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00538

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00281

AC:

706

AN:

251212

Hom.:

AF XY:

0.00281

AC XY:

382

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00234

Gnomad ASJ exome

AF:

0.00367

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.00469

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00392

AC:

5730

AN:

1461686

Hom.:

Cov.:

AF XY:

0.00386

AC XY:

2808

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.000807

Gnomad4 AMR exome

AF:

0.00273

Gnomad4 ASJ exome

AF:

0.00467

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.000412

Gnomad4 NFE exome

AF:

0.00466

Gnomad4 OTH exome

AF:

0.00383

GnomAD4 genome

AF:

0.00334

AC:

509

AN:

152210

Hom.:

Cov.:

AF XY:

0.00301

AC XY:

224

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.000987

Gnomad4 AMR

AF:

0.00419

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00538

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00512

Hom.:

Bravo

AF:

0.00365

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00270

AC:

328

EpiCase

AF:

0.00496

EpiControl

AF:

0.00492

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	FGG: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The FGG p.Gly191Arg variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs6063) as "With Pathogenic allele" and in ClinVar (variant classified as pathogenic by OMIM; associated condition is digenic Fibrinogen Milano XII) The variant was identified in control databases in 784 of 282600 chromosomes (4 homozygous) at a frequency of 0.002774 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 596 of 128994 chromosomes (freq: 0.00462), Ashkenazi Jewish in 39 of 10360 chromosomes (freq: 0.003764), Other in 26 of 7216 chromosomes (freq: 0.003603), Latino in 85 of 35390 chromosomes (freq: 0.002402), African in 23 of 24960 chromosomes (freq: 0.000922), European (Finnish) in 11 of 25120 chromosomes (freq: 0.000438) and South Asian in 4 of 30610 chromosomes (freq: 0.000131), while the variant was not observed in the and East Asian population. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Gly191 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the G variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 27, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 22, 2024	Variant summary: FGG c.571G>A (p.Gly191Arg) results in a non-conservative amino acid change located in the Fibrinogen, alpha/beta/gamma chain, C-terminal globular domain (IPR002181) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 251212 control chromosomes in the gnomAD database, including 3 homozygotes. c.571G>A has been reported in the literature in individuals affected with thrombotic disorder or HELLP syndrome without evidence of causality (e.g. Downes_2019, Jimenez_2020). These reports do not provide unequivocal conclusions about association of the variant with Congenital Dysfibrinogenemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31064749, 33059327). ClinVar contains an entry for this variant (Variation ID: 16378). Based on the evidence outlined above, the variant was classified as likely benign. -

Fibrinogen Milano XII, digenic

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 15, 2001

- -

Hypofibrinogenemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Familial dysfibrinogenemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

- -

Congenital afibrinogenemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

.;.;D;T;T;T

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

MetaRNN

Benign

0.016

T;T;T;T;T;T

MetaSVM

Uncertain

0.71

MutationAssessor

Pathogenic

3.6

H;.;H;.;.;.

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.6

D;D;D;D;D;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.012

D;D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;.;.

Vest4

0.97

MutPred

0.69

.;Loss of ubiquitination at K196 (P = 0.0331);.;Loss of ubiquitination at K196 (P = 0.0331);.;.;

MVP

0.98

MPC

0.88

ClinPred

0.052

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.93

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over