4-154604543-G-A

Position:

• chr4-154604543-G-A

Variant summary

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

The NM_021870.3(FGG):​c.*291C>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 0.238 in 1,118,258 control chromosomes in the GnomAD database, including 33,616 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5622 hom., cov: 32)
  • Exomes 𝑓: 0.23 (27994 hom.)
• Consequence: FGG NM_021870.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.81

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 4-154604543-G-A is Benign according to our data. Variant chr4-154604543-G-A is described in ClinVar as [Benign]. Clinvar id is 1271870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.429 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGG	NM_021870.3	c.*291C>T		3_prime_UTR_variant	9/9	ENST00000336098.8	NP_068656.2
FGG	NM_000509.6	c.1300-189C>T		intron_variant			NP_000500.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGG	ENST00000336098.8	c.*291C>T		3_prime_UTR_variant	9/9	2	NM_021870.3	ENSP00000336829

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40297 AN: 151714 Hom.: 5614 Cov.: 32

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.445

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.163

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.227

GnomAD4 exome AF: 0.234 AC: 225792 AN: 966424 Hom.: 27994 Cov.: 14 AF XY: 0.235 AC XY: 111301 AN XY: 473198

Gnomad4 AFR exome AF: 0.286

Gnomad4 AMR exome AF: 0.212

Gnomad4 ASJ exome AF: 0.145

Gnomad4 EAS exome AF: 0.467

Gnomad4 SAS exome AF: 0.299

Gnomad4 FIN exome AF: 0.304

Gnomad4 NFE exome AF: 0.220

Gnomad4 OTH exome AF: 0.223

GnomAD4 genome AF: 0.266 AC: 40337 AN: 151834 Hom.: 5622 Cov.: 32 AF XY: 0.268 AC XY: 19862 AN XY: 74216

Gnomad4 AFR AF: 0.301

Gnomad4 AMR AF: 0.222

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.444

Gnomad4 SAS AF: 0.294

Gnomad4 FIN AF: 0.298

Gnomad4 NFE AF: 0.242

Gnomad4 OTH AF: 0.226

Alfa AF: 0.162 Hom.: 373

Bravo AF: 0.263

Asia WGS AF: 0.317 AC: 1083 AN: 3432

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.6
DANN	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs2066864; hg19: chr4-155525695;