rs121913091

Positions:

• chr4-154606827-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_021870.3(FGG):​c.1007T>C​(p.Met336Thr) 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: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 9.05

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 4-154606827-A-G is Pathogenic according to our data. Variant chr4-154606827-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGG	NM_021870.3	c.1007T>C	p.Met336Thr	missense_variant	8/9	ENST00000336098.8	NP_068656.2
FGG	NM_000509.6	c.1007T>C	p.Met336Thr	missense_variant	8/10		NP_000500.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGG	ENST00000336098.8	c.1007T>C	p.Met336Thr	missense_variant	8/9	2	NM_021870.3	ENSP00000336829

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FGG-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 2022

The FGG c.1007T>C variant is predicted to result in the amino acid substitution p.Met336Thr. This variant, also known as Met310Thr by legacy nomenclature, has been reported in individuals with Dysfibrinogenemia (Yamazumi et al. 1989. PubMed ID: 2496144; Park et al. 2009. PubMed ID: 19949684; Miesbach et al 2010. PubMed ID: 19923982; Shigekiyo et al. 2012. PubMed ID: 22836217). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Familial dysfibrinogenemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 16, 2021

Variant summary: FGG c.1007T>C (p.Met336Thr) (legacy name p.Met310Thr) results in a non-conservative amino acid change located in the Fibrinogen, alpha/beta/gamma chain, C-terminal globular domain (IPR002181) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251364 control chromosomes. c.1007T>C has been reported in the literature with different common names such as Fibrinogen Asahi, Fibrinogen Yecheon, Fibrinogen Tokushima II in individuals affected with Congenital Dysfibrinogenemia (example, Yamazumi_1989, Park_2009, Shigekiyo_2012, Miesbach_2010). Some of these reports indicated this variant as a heterozygous de-novo occurrence in the affected proband. It is known to result in subsequent extra N-glycosylation at the gamma Asn 308 (Yamazumi_1989). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

FIBRINOGEN ASAHI Other:1

other, no assertion criteria provided

literature only

OMIM

Sep 26, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	.;.;T;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.4	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.4	D;D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.020	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.96
MutPred		0.73		.;Loss of stability (P = 0.0575);.;Loss of stability (P = 0.0575);
MVP		0.97
MPC		0.86
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.96

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: rs121913091; hg19: chr4-155527979;