15-48487362-C-T
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_000138.5(FBN1):c.3413G>A(p.Cys1138Tyr) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1138F) 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: 7.38
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 13 ACMG points.
PM1
In a disulfide_bond (size 14) in uniprot entity FBN1_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) 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 chr15-48487362-C-A is described in Lovd as [Likely_pathogenic].
PP2
Missense variant in the FBN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 1311 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.0644 (above the threshold of 3.09). Trascript score misZ: 8.1787 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.996
PP5
Variant 15-48487362-C-T is Pathogenic according to our data. Variant chr15-48487362-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 667006.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Marfan syndrome Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 07, 2018 | The p.Cys1138Tyr variant in FBN1 has been reported in an individual with clinica l features of Marfan syndrome (Comeglio 2007) and was absent from large populati on studies. Computational prediction tools and conservation analysis suggest tha t the p.Cys1138Tyr variant may impact the protein. Additional missense variants at this amino acid position (p.Cys1138Phe, p.Cys1138Arg, p.Cys1138Gly, and p.Cys 1138Ser) have been reported in association with Marfan syndrome or other FBN1-re lated disorders (Stheneur 2009, Lerner-Ellis 2014, UMD-FBN1 database; Collod-Ber oud 2003), suggesting that changes at this position in not tolerated. Additiona lly, the p.Cys1138Tyr variant affects a cysteine residue within a calcium-bindin g EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is pr edicted to alter the structure and function of the protein. Cysteine substitutio ns in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Vollbrandt 2004). In summary, although additional studies are required to fully establish its clinical signifi cance, the p.Cys1138Tyr variant is likely pathogenic. ACMG/AMP Criteria applied (Richards 2015): PS4-Supporting, PM1, PM2, PP3. - |
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
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Vest4
MutPred
Loss of disorder (P = 0.0879);
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