rs1553965518

Positions:

• chr4-154606804-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_021870.3(FGG):​c.1030G>A​(p.Asp344Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGG NM_021870.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.67

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity FIBG_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 4-154606804-C-T is Pathogenic according to our data. Variant chr4-154606804-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521192.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGG	NM_021870.3	c.1030G>A	p.Asp344Asn	missense_variant	8/9	ENST00000336098.8	NP_068656.2
FGG	NM_000509.6	c.1030G>A	p.Asp344Asn	missense_variant	8/10		NP_000500.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGG	ENST00000336098.8	c.1030G>A	p.Asp344Asn	missense_variant	8/9	2	NM_021870.3	ENSP00000336829

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2023

The c.1030G>A (p.D344N) alteration is located in exon 8 (coding exon 8) of the FGG gene. This alteration results from a G to A substitution at nucleotide position 1030, causing the aspartic acid (D) at amino acid position 344 to be replaced by an asparagine (N). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was identified in a patient with abdominal pain, history of ischemic stroke, a partially thrombosed abdominal aortic aneurysm, prolonged lengthened thrombin time, and a significant decrease in fibrinogen concentration (Tamayo-Velasco, 2022). Three other alterations at the same codon, c.1031A>G (p.D344G), c.1030G>T (p.D344Y), and c.1031A>T (p.D344V), have been reported in a patient with hypofibrinogenemia and an episode of venous thrombosis at age 18 years (Haverkate, 1995), a patient with severely prolonged plasma thrombin clotting time and low plasma fibrinogen concentration (Lounes, 1999), and a child with hypofibrinogenemia (Robert-Ebadi, 2008), respectively. This amino acid position is highly conserved in available vertebrate species. The p.D344 amino acid is located in the D-domain Ca2+ binding site of the fibrinogen gamma chain (Dang, 1985). The binding of Ca2+ to fibrinogen is necessary for proper function. The fibrinogen gamma chain Ca2+ binding motif is located between amino acid residues 341 - 354 (WDNDNDKFEGNCAE) and is highly homologous to the Ca2+ binding site of calmodulin and parvalbumin (Dang, 1985). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	.;.;T;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.8	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.020	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.90
MutPred		0.91		.;Gain of methylation at K355 (P = 0.0936);.;Gain of methylation at K355 (P = 0.0936);
MVP		0.99
MPC		0.79
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		0.99

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: rs1553965518; hg19: chr4-155527956;