rs2066865

Positions:

• chr4-154604124-G-A
• chr4-154604124-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The 4-154604124-G-A variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 414,858 control chromosomes in the GnomAD database, including 15,657 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5650 hom., cov: 32)
  • Exomes 𝑓: 0.26 (10007 hom.)
• Consequence: FGG NM_021870.3 downstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.104

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-154604124-G-A is Benign according to our data. Variant chr4-154604124-G-A is described in ClinVar as [Benign]. Clinvar id is 369438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGG	NM_021870.3			downstream_gene_variant		ENST00000336098.8
FGG	NM_000509.6			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGG	ENST00000336098.8			downstream_gene_variant		2	NM_021870.3

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40402 AN: 151920 Hom.: 5640 Cov.: 32

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.446

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.227

GnomAD4 exome AF: 0.262 AC: 68902 AN: 262820 Hom.: 10007 Cov.: 4 AF XY: 0.261 AC XY: 34854 AN XY: 133778

Gnomad4 AFR exome AF: 0.289

Gnomad4 AMR exome AF: 0.211

Gnomad4 ASJ exome AF: 0.150

Gnomad4 EAS exome AF: 0.486

Gnomad4 SAS exome AF: 0.293

Gnomad4 FIN exome AF: 0.303

Gnomad4 NFE exome AF: 0.235

Gnomad4 OTH exome AF: 0.238

GnomAD4 genome AF: 0.266 AC: 40446 AN: 152038 Hom.: 5650 Cov.: 32 AF XY: 0.268 AC XY: 19914 AN XY: 74332

Gnomad4 AFR AF: 0.302

Gnomad4 AMR AF: 0.222

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.446

Gnomad4 SAS AF: 0.294

Gnomad4 FIN AF: 0.295

Gnomad4 NFE AF: 0.242

Gnomad4 OTH AF: 0.226

Alfa AF: 0.237 Hom.: 5923

Bravo AF: 0.263

Asia WGS AF: 0.318 AC: 1104 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital afibrinogenemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

This variant is associated with the following publications: (PMID: 31582554, 16144795, 17445871, 19492150, 17403086, 25772935) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.4
DANN	Benign	0.58

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2066865; hg19: chr4-155525276;