rs191297318

Variant names:

• chr4-154604346-G-A
• rs191297318
• ENST00000404648.7:c.1308C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000509.6(FGG):​c.1308C>T​(p.Asp436Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,510,082 control chromosomes in the GnomAD database, including 100 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 0.0042 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (82 hom.)
• Consequence: FGG NM_000509.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.393
• Publications: 0 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 4-154604346-G-A is Benign according to our data. Variant chr4-154604346-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 347825.
• BP7: Synonymous conserved (PhyloP=0.393 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00419 (638/152164) while in subpopulation NFE AF = 0.00134 (91/67988). AF 95% confidence interval is 0.00112. There are 18 homozygotes in GnomAd4. There are 452 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 SD,AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000509.6. 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.*488C>T		3_prime_UTR	Exon 9 of 9	NP_068656.2	P02679-1
	FGG	NM_000509.6		c.1308C>T	p.Asp436Asp	synonymous	Exon 10 of 10	NP_000500.2	P02679-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGG	ENST00000404648.7	TSL:1	c.1308C>T	p.Asp436Asp	synonymous	Exon 10 of 10	ENSP00000384860.3	P02679-2
	FGG	ENST00000336098.8	TSL:2 MANE Select	c.*488C>T		3_prime_UTR	Exon 9 of 9	ENSP00000336829.3	P02679-1
	FGG	ENST00000405164.5	TSL:5	c.1332C>T	p.Asp444Asp	synonymous	Exon 10 of 10	ENSP00000384101.1	C9JEU5

Frequencies

GnomAD3 genomes AF: 0.00420 AC: 638 AN: 152046 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0510

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00728 AC: 935 AN: 128374 AF XY: 0.00670

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0535

Gnomad NFE exome AF: 0.000477

Gnomad OTH exome AF: 0.00400

GnomAD4 exome AF: 0.00210 AC: 2850 AN: 1357918 Hom.: 82 Cov.: 27 AF XY: 0.00207 AC XY: 1388 AN XY: 669276

African (AFR) AF: 0.0000349 AC: 1 AN: 28642

American (AMR) AF: 0.000113 AC: 3 AN: 26522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24218

East Asian (EAS) AF: 0.00 AC: 0 AN: 33992

South Asian (SAS) AF: 0.0000575 AC: 4 AN: 69568

European-Finnish (FIN) AF: 0.0493 AC: 2420 AN: 49088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5584

European-Non Finnish (NFE) AF: 0.000294 AC: 313 AN: 1063924

Other (OTH) AF: 0.00193 AC: 109 AN: 56380

GnomAD4 genome AF: 0.00419 AC: 638 AN: 152164 Hom.: 18 Cov.: 33 AF XY: 0.00608 AC XY: 452 AN XY: 74394

African (AFR) AF: 0.0000241 AC: 1 AN: 41528

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.0510 AC: 539 AN: 10572

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

European-Non Finnish (NFE) AF: 0.00134 AC: 91 AN: 67988

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00134 Hom.: 2

Bravo AF: 0.000287

Asia WGS AF: 0.000868 AC: 3 AN: 3470

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital afibrinogenemia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	4.8
DANN	Benign	0.59
PhyloP100		0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs191297318; hg19: chr4-155525498;