4-154606882-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_021870.3(FGG):​c.952G>A​(p.Gly318Ser) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G318R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

FGG
NM_021870.3 missense

Scores

10
7
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.67

Publications

1 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1
In a domain Fibrinogen C-terminal (size 246) in uniprot entity FIBG_HUMAN there are 19 pathogenic changes around while only 2 benign (90%) in NM_021870.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FGGNM_021870.3 linkc.952G>A p.Gly318Ser missense_variant Exon 8 of 9 ENST00000336098.8 NP_068656.2 P02679-1
FGGNM_000509.6 linkc.952G>A p.Gly318Ser missense_variant Exon 8 of 10 NP_000500.2 P02679-2A0A140VJJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FGGENST00000336098.8 linkc.952G>A p.Gly318Ser missense_variant Exon 8 of 9 2 NM_021870.3 ENSP00000336829.3 P02679-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hypofibrinogenemia Uncertain:1
Feb 01, 2019
NIHR Bioresource Rare Diseases, University of Cambridge
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.33
.;.;T;T
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.95
D;D;D;D
M_CAP
Pathogenic
0.47
D
MetaRNN
Pathogenic
0.89
D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.1
M;.;M;.
PhyloP100
7.7
PrimateAI
Uncertain
0.73
T
PROVEAN
Uncertain
-3.4
D;D;D;D
REVEL
Pathogenic
0.82
Sift
Uncertain
0.0040
D;D;D;D
Sift4G
Uncertain
0.011
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.81
MutPred
0.53
.;Gain of phosphorylation at G326 (P = 0.0321);.;Gain of phosphorylation at G326 (P = 0.0321);
MVP
0.99
MPC
0.80
ClinPred
0.99
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.68
gMVP
0.90
Mutation Taster
=9/91
disease causing

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

Other links and lift over

dbSNP: rs267606810; hg19: chr4-155528034; COSMIC: COSV100272138; COSMIC: COSV100272138; API