chr4-154604543-G-A

Variant names:

• chr4-154604543-G-A
• rs2066864
• NM_021870.3:c.*291C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 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 -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 VariationId 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 rank	MANE	Protein	UniProt
FGG	NM_021870.3	c.*291C>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000336098.8	NP_068656.2
FGG	NM_000509.6	c.1300-189C>T		intron_variant	Intron 9 of 9		NP_000500.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGG	ENST00000336098.8	c.*291C>T		3_prime_UTR_variant	Exon 9 of 9	2	NM_021870.3	ENSP00000336829.3

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

African (AFR) AF: 0.286 AC: 5658 AN: 19768

American (AMR) AF: 0.212 AC: 2635 AN: 12418

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 2331 AN: 16080

East Asian (EAS) AF: 0.467 AC: 13675 AN: 29256

South Asian (SAS) AF: 0.299 AC: 11197 AN: 37400

European-Finnish (FIN) AF: 0.304 AC: 10268 AN: 33802

Middle Eastern (MID) AF: 0.173 AC: 510 AN: 2942

European-Non Finnish (NFE) AF: 0.220 AC: 170234 AN: 773186

Other (OTH) AF: 0.223 AC: 9284 AN: 41572

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

African (AFR) AF: 0.301 AC: 12438 AN: 41384

American (AMR) AF: 0.222 AC: 3381 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 494 AN: 3460

East Asian (EAS) AF: 0.444 AC: 2295 AN: 5164

South Asian (SAS) AF: 0.294 AC: 1419 AN: 4822

European-Finnish (FIN) AF: 0.298 AC: 3131 AN: 10522

Middle Eastern (MID) AF: 0.161 AC: 47 AN: 292

European-Non Finnish (NFE) AF: 0.242 AC: 16423 AN: 67914

Other (OTH) AF: 0.226 AC: 476 AN: 2110

Alfa AF: 0.169 Hom.: 405

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.6
DANN	Benign	0.65
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs2066864; hg19: chr4-155525695;