rs148685782

Variant names:

• chr4-154611883-G-C
• rs148685782
• NM_021870.3:c.323C>G
• FGG p.Ala108Gly

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 4P and 12B. PS3 BP4_Strong BS1 BS2

The NM_021870.3(FGG):​c.323C>G​(p.Ala108Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00303 in 1,611,606 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV001249260: PS3:Supporting".

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (12 hom.)
• Consequence: FGG NM_021870.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:16 U:5 B:1
• Conservation: PhyloP100: 1.97
• Publications: 29 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)
• congenital afibrinogenemia

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

  Inheritance: AR, AD Classification: STRONG Submitted by: Genomics England PanelApp
• familial hypofibrinogenemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001249260: PS3:Supporting
• BP4: Computational evidence support a benign effect (MetaRNN=0.011885256).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00217 (331/152266) while in subpopulation NFE AF = 0.00404 (275/68018). AF 95% confidence interval is 0.00365. There are 0 homozygotes in GnomAd4. There are 128 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 AD,AR,SD 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.323C>G	p.Ala108Gly	missense	Exon 4 of 9	NP_068656.2	P02679-1
	FGG	NM_000509.6		c.323C>G	p.Ala108Gly	missense	Exon 4 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.323C>G	p.Ala108Gly	missense	Exon 4 of 9	ENSP00000336829.3	P02679-1
	FGG	ENST00000404648.7	TSL:1	c.323C>G	p.Ala108Gly	missense	Exon 4 of 10	ENSP00000384860.3	P02679-2
	FGG	ENST00000407946.5	TSL:5	c.323C>G	p.Ala108Gly	missense	Exon 4 of 9	ENSP00000384552.1	C9JC84

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 332 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00406

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00195 AC: 486 AN: 249532 AF XY: 0.00210

Gnomad AFR exome AF: 0.000804

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00123

Gnomad NFE exome AF: 0.00355

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.00312 AC: 4554 AN: 1459340 Hom.: 12 Cov.: 30 AF XY: 0.00322 AC XY: 2338 AN XY: 726064

African (AFR) AF: 0.000718 AC: 24 AN: 33430

American (AMR) AF: 0.000672 AC: 30 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00161 AC: 42 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.000592 AC: 51 AN: 86142

European-Finnish (FIN) AF: 0.00106 AC: 56 AN: 52700

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5756

European-Non Finnish (NFE) AF: 0.00383 AC: 4251 AN: 1110770

Other (OTH) AF: 0.00161 AC: 97 AN: 60276

GnomAD4 genome AF: 0.00217 AC: 331 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.00172 AC XY: 128 AN XY: 74446

African (AFR) AF: 0.000529 AC: 22 AN: 41564

American (AMR) AF: 0.000654 AC: 10 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10596

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00404 AC: 275 AN: 68018

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00321 Hom.: 1

Bravo AF: 0.00187

EpiCase AF: 0.00366

EpiControl AF: 0.00399

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	1	-	Congenital afibrinogenemia (5)
4	-	1	not provided (5)
3	-	-	Familial dysfibrinogenemia (3)
1	1	-	Hereditary factor I deficiency disease (2)
-	2	-	not specified (2)
1	-	-	Abnormal bleeding (1)
1	-	-	Familial dysfibrinogenemia;C2584774:Congenital afibrinogenemia (1)
-	1	-	FGG-related disorder (1)
1	-	-	Thrombocytopenia;C1458140:Abnormal bleeding (1)
1	-	-	Thrombus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	18
DANN	Benign	0.90
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.46
Sift	Benign	0.34	T
Sift4G	Benign	0.34	T
Varity_R		0.19
gMVP		0.34
Mutation Taster		=3/97	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs148685782;

hg19: chr4-155533035;

COSMIC: COSV108145347;