rs1064794882
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Moderate
The NM_000138.5(FBN1):c.3380G>T(p.Gly1127Val) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1127D) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
FBN1
NM_000138.5 missense
NM_000138.5 missense
Scores
14
2
1
Clinical Significance
Conservation
PhyloP100: 5.68
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 Pathogenic. Variant got 11 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000138.5
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr15-48487395-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 495589.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.
PP2
?
Missense variant where missense usually causes diseases, FBN1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.937
PP5
?
Variant 15-48487395-C-A is Pathogenic according to our data. Variant chr15-48487395-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 421062.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-48487395-C-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.3380G>T | p.Gly1127Val | missense_variant | 28/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.3380G>T | p.Gly1127Val | missense_variant | 27/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.3380G>T | p.Gly1127Val | missense_variant | 28/66 | 1 | NM_000138.5 | 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: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 12, 2016 | The G1127V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant has been reported in the Universal Mutation Database in one French male proband with familial Marfan syndrome (Beroud et al., 2000); however, no specific clinical or family history information was provided. In addition, a different missense variant affecting the same residue (G1127S) was identified in 9 out of 10 individuals with ascending aortic disease from one family, and one young unaffected family member (Francke et al., 1995). This variant was not observed in any other unaffected family members or in 168 control chromosomes (Francke et al., 1995).The G1127V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although the G1127V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs at a position that is conserved across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, although the G1127V variant occurs within a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a Cysteine residue. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003). Nevertheless, Khau et al. (2010) studied Glycine substitutions at the 3rd position of a 4 amino acid loop-region of the calcium-binding EGF-like domain and concluded that steric strain allows only Glycine or Alanine residues at this position for the maintenance of domain structure and fibrillin function. Furthermore, Whiteman et al. (1998) demonstrated that G1127 residue is crucial for folding of the FBN1 calcium-binding EGF-like domain.Therefore, this variant is likely pathogenic. - |
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
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Vest4
MutPred
Loss of disorder (P = 0.0384);
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