rs6063

chr4-154609725-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1 PP3 BP4_Strong BP6 BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G191E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (19 hom.)
• Consequence: FGG NM_021870.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:3
• Conservation: PhyloP100: 7.62

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM1: In a domain Fibrinogen C-terminal (size 246) in uniprot entity FIBG_HUMAN there are 22 pathogenic changes around while only 7 benign (76%) in NM_021870.3
• 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=2, Uncertain_significance=3, Benign=1}.
• BS2: High Homozygotes in GnomAd at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGG	NM_021870.3	c.571G>A	p.Gly191Arg	missense_variant	6/9	ENST00000336098.8
FGG	NM_000509.6	c.571G>A	p.Gly191Arg	missense_variant	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGG	ENST00000336098.8	c.571G>A	p.Gly191Arg	missense_variant	6/9	2	NM_021870.3

Frequencies

GnomAD3 genomes AF: 0.00335 AC: 509 AN: 152092 Hom.: 2 Cov.: 32

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.: 3 AF XY: 0.00281 AC XY: 382 AN XY: 135764

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.: 19 Cov.: 31 AF XY: 0.00386 AC XY: 2808 AN XY: 727144

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.: 2 Cov.: 32 AF XY: 0.00301 AC XY: 224 AN XY: 74412

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.: 4

Bravo AF: 0.00365

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00270 AC: 328

EpiCase AF: 0.00496

EpiControl AF: 0.00492

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

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. -
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	Invitae	Jan 18, 2024	- -

Fibrinogen Milano XII, digenic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 15, 2001

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Apr 27, 2019

- -

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	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
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	D
MutationAssessor	Pathogenic	3.6	H;.;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
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	T
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

Other links and lift over

dbSNP: rs6063; hg19: chr4-155530877;