rs6063

Variant names:

• chr4-154609725-C-T
• rs6063
• NM_021870.3:c.571G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-154609725-C-T
• chr4-154609725-C-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 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:5 B:4
• Conservation: PhyloP100: 7.62
• Publications: 23 publications found

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 Gene-Disease associations (from GenCC):

• congenital fibrinogen deficiency

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• familial dysfibrinogenemia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• 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 hypofibrinogenemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, REVEL, 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 VariationId is 16378.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00334 (509/152210) while in subpopulation NFE AF = 0.00538 (366/67994). AF 95% confidence interval is 0.00493. There are 2 homozygotes in GnomAd4. There are 224 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 SD,AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021870.3. 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
	FGG	NM_021870.3	MANE Select	c.571G>A	p.Gly191Arg	missense	Exon 6 of 9	NP_068656.2	P02679-1
	FGG	NM_000509.6		c.571G>A	p.Gly191Arg	missense	Exon 6 of 10	NP_000500.2	P02679-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGG	ENST00000336098.8	TSL:2 MANE Select	c.571G>A	p.Gly191Arg	missense	Exon 6 of 9	ENSP00000336829.3	P02679-1
	FGG	ENST00000404648.7	TSL:1	c.571G>A	p.Gly191Arg	missense	Exon 6 of 10	ENSP00000384860.3	P02679-2
	FGG	ENST00000407946.5	TSL:5	c.595G>A	p.Gly199Arg	missense	Exon 6 of 9	ENSP00000384552.1	C9JC84

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

GnomAD2 exomes AF: 0.00281 AC: 706 AN: 251212 AF XY: 0.00281

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 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

African (AFR) AF: 0.000807 AC: 27 AN: 33466

American (AMR) AF: 0.00273 AC: 122 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00467 AC: 122 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86256

European-Finnish (FIN) AF: 0.000412 AC: 22 AN: 53406

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5766

European-Non Finnish (NFE) AF: 0.00466 AC: 5176 AN: 1111896

Other (OTH) AF: 0.00383 AC: 231 AN: 60388

GnomAD4 genome AF: 0.00334 AC: 509 AN: 152210 Hom.: 2 Cov.: 32 AF XY: 0.00301 AC XY: 224 AN XY: 74412

African (AFR) AF: 0.000987 AC: 41 AN: 41544

American (AMR) AF: 0.00419 AC: 64 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10598

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00538 AC: 366 AN: 67994

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00498 Hom.: 8

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	1	1	not specified (2)
-	-	1	Congenital afibrinogenemia (1)
-	1	-	Familial dysfibrinogenemia (1)
1	-	-	Fibrinogen Milano XII, digenic (1)
-	1	-	Hypofibrinogenemia (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Uncertain	0.50	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.69		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
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs6063; hg19: chr4-155530877; COSMIC: COSV107431325; COSMIC: COSV107431325;