4-154604340-T-C

Variant names:

• chr4-154604340-T-C
• rs1731056413
• ENST00000404648.7:c.1314A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_000509.6(FGG):​c.1314A>G​(p.Ter438Ter) variant causes a stop retained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FGG NM_000509.6 stop_retained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae)
• thrombophilia

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• familial hypofibrinogenemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP7: Synonymous conserved (PhyloP=1.03 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000509.6. 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.*494A>G		3_prime_UTR	Exon 9 of 9	NP_068656.2	P02679-1
	FGG	NM_000509.6		c.1314A>G	p.Ter438Ter	stop_retained	Exon 10 of 10	NP_000500.2	P02679-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGG	ENST00000404648.7	TSL:1	c.1314A>G	p.Ter438Ter	stop_retained	Exon 10 of 10	ENSP00000384860.3	P02679-2
	FGG	ENST00000336098.8	TSL:2 MANE Select	c.*494A>G		3_prime_UTR	Exon 9 of 9	ENSP00000336829.3	P02679-1
	FGG	ENST00000405164.5	TSL:5	c.1338A>G	p.Ter446Ter	stop_retained	Exon 10 of 10	ENSP00000384101.1	C9JEU5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1363024 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 671914

African (AFR) AF: 0.00 AC: 0 AN: 29046

American (AMR) AF: 0.00 AC: 0 AN: 27846

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24376

East Asian (EAS) AF: 0.00 AC: 0 AN: 34238

South Asian (SAS) AF: 0.00 AC: 0 AN: 70432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5598

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1065588

Other (OTH) AF: 0.00 AC: 0 AN: 56580

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital afibrinogenemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Benign	0.76
PhyloP100		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1731056413; hg19: chr4-155525492;