rs2066879

Variant names:

• chr4-154604563-G-A
• rs2066879
• NM_021870.3:c.*271C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_021870.3(FGG):​c.*271C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00242 in 1,151,626 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.012 (28 hom., cov: 33)
  • Exomes 𝑓: 0.00095 (18 hom.)
• Consequence: FGG NM_021870.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.772
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Orphanet
• thrombophilia

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
• congenital afibrinogenemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• 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=-0.82).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.012 (1833/152136) while in subpopulation AFR AF = 0.0417 (1732/41526). AF 95% confidence interval is 0.0401. There are 28 homozygotes in GnomAd4. There are 860 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 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.*271C>T		3_prime_UTR	Exon 9 of 9	NP_068656.2
	FGG	NM_000509.6		c.1300-209C>T		intron	N/A	NP_000500.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGG	ENST00000336098.8	TSL:2 MANE Select	c.*271C>T		3_prime_UTR	Exon 9 of 9	ENSP00000336829.3
	FGG	ENST00000404648.7	TSL:1	c.1300-209C>T		intron	N/A	ENSP00000384860.3
	FGG	ENST00000405164.5	TSL:5	c.1324-209C>T		intron	N/A	ENSP00000384101.1

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1833 AN: 152018 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.0418

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00717

GnomAD4 exome AF: 0.000950 AC: 950 AN: 999490 Hom.: 18 Cov.: 15 AF XY: 0.000871 AC XY: 426 AN XY: 489160

African (AFR) AF: 0.0365 AC: 756 AN: 20710

American (AMR) AF: 0.00251 AC: 32 AN: 12734

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16338

East Asian (EAS) AF: 0.00 AC: 0 AN: 29786

South Asian (SAS) AF: 0.000150 AC: 6 AN: 40046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31880

Middle Eastern (MID) AF: 0.00167 AC: 5 AN: 2996

European-Non Finnish (NFE) AF: 0.0000648 AC: 52 AN: 802188

Other (OTH) AF: 0.00231 AC: 99 AN: 42812

GnomAD4 genome AF: 0.0120 AC: 1833 AN: 152136 Hom.: 28 Cov.: 33 AF XY: 0.0116 AC XY: 860 AN XY: 74388

African (AFR) AF: 0.0417 AC: 1732 AN: 41526

American (AMR) AF: 0.00425 AC: 65 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

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

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 67990

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00943 Hom.: 1

Bravo AF: 0.0134

Asia WGS AF: 0.00146 AC: 5 AN: 3446

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.5
DANN	Benign	0.60
PhyloP100		-0.77
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs2066879; hg19: chr4-155525715;