rs397515849
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_000138.5(FBN1):c.7184G>T(p.Gly2395Val) 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 (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
FBN1
NM_000138.5 missense
NM_000138.5 missense
Scores
11
5
1
Clinical Significance
Conservation
PhyloP100: 7.91
Genes affected
FBN1 (HGNC:3603): (fibrillin 1) This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN1. . Gene score misZ 5.0644 (greater than the threshold 3.09). Trascript score misZ 8.1787 (greater than threshold 3.09). GenCC has associacion of gene with MASS syndrome, Weill-Marchesani syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, Acromicric dysplasia, familial thoracic aortic aneurysm and aortic dissection, progeroid and marfanoid aspect-lipodystrophy syndrome, ectopia lentis 1, isolated, autosomal dominant, Marfan syndrome, Weill-Marchesani syndrome 2, dominant, isolated ectopia lentis, neonatal Marfan syndrome, stiff skin syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.938
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.7184G>T | p.Gly2395Val | missense_variant | 58/66 | ENST00000316623.10 | NP_000129.3 | |
FBN1 | NM_001406716.1 | c.7184G>T | p.Gly2395Val | missense_variant | 57/65 | NP_001393645.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.7184G>T | p.Gly2395Val | missense_variant | 58/66 | 1 | NM_000138.5 | ENSP00000325527 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 14, 2012 | Variant classified as Uncertain Significance - Favor Pathogenic. The Gly2395Val variant in FBN1 has not been reported in the literature nor previously identifie d by our laboratory. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Gly2395Val varian t may impact the protein, though this information is not predictive enough to de termine pathogenicity. In summary, additional information is needed to fully ass ess the clinical significance of the Gly2395Val variant. - |
Marfan syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Center for Medical Genetics Ghent, University of Ghent | Nov 07, 2017 | - - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 06, 2017 | The p.G2395V variant (also known as c.7184G>T), located in coding exon 57 of the FBN1 gene, results from a G to T substitution at nucleotide position 7184. The glycine at codon 2395 is replaced by valine, an amino acid with dissimilar properties, and is located in the TGFBP #07 domain. This alteration has been reported in an individual with some Marfan-like features; however, clinical details were limited (Lerner-Ellis JP et al. Mol. Genet. Metab., 2014 Jun;112:171-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2021 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of FBN1-related disease (PMID: 24793577, Invitae). ClinVar contains an entry for this variant (Variation ID: 42423). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 2395 of the FBN1 protein (p.Gly2395Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Vest4
MutPred
Loss of methylation at R2394 (P = 0.0942);
MVP
MPC
ClinPred
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at