4-154608322-C-T

Variant names:

• chr4-154608322-C-T
• rs2066860
• NM_021870.3:c.851+144G>A

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.851+144G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0267 in 810,540 control chromosomes in the GnomAD database, including 379 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 0.022 (50 hom., cov: 32)
  • Exomes 𝑓: 0.028 (329 hom.)
• Consequence: FGG NM_021870.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.284
• Publications: 8 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=-0.81).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0223 (3393/152232) while in subpopulation NFE AF = 0.0362 (2459/68008). AF 95% confidence interval is 0.035. There are 50 homozygotes in GnomAd4. There are 1565 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 SD,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGG	NM_021870.3	c.851+144G>A		intron_variant	Intron 7 of 8	ENST00000336098.8	NP_068656.2
FGG	NM_000509.6	c.851+144G>A		intron_variant	Intron 7 of 9		NP_000500.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGG	ENST00000336098.8	c.851+144G>A		intron_variant	Intron 7 of 8	2	NM_021870.3	ENSP00000336829.3

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3395 AN: 152114 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.00623

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0217

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.0165

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.0362

Gnomad OTH AF: 0.0263

GnomAD4 exome AF: 0.0277 AC: 18246 AN: 658308 Hom.: 329 AF XY: 0.0268 AC XY: 9293 AN XY: 346610

African (AFR) AF: 0.00570 AC: 100 AN: 17556

American (AMR) AF: 0.0134 AC: 436 AN: 32630

Ashkenazi Jewish (ASJ) AF: 0.0250 AC: 465 AN: 18580

East Asian (EAS) AF: 0.0000926 AC: 3 AN: 32412

South Asian (SAS) AF: 0.00334 AC: 197 AN: 58934

European-Finnish (FIN) AF: 0.0215 AC: 722 AN: 33514

Middle Eastern (MID) AF: 0.0166 AC: 43 AN: 2588

European-Non Finnish (NFE) AF: 0.0361 AC: 15482 AN: 428534

Other (OTH) AF: 0.0238 AC: 798 AN: 33560

GnomAD4 genome AF: 0.0223 AC: 3393 AN: 152232 Hom.: 50 Cov.: 32 AF XY: 0.0210 AC XY: 1565 AN XY: 74430

African (AFR) AF: 0.00621 AC: 258 AN: 41542

American (AMR) AF: 0.0217 AC: 331 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 96 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4832

European-Finnish (FIN) AF: 0.0165 AC: 175 AN: 10602

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.0362 AC: 2459 AN: 68008

Other (OTH) AF: 0.0260 AC: 55 AN: 2114

Alfa AF: 0.0342 Hom.: 139

Bravo AF: 0.0225

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.4
DANN	Benign	0.46
PhyloP100		0.28
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: rs2066860; hg19: chr4-155529474;