rs193922236
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000138.5(FBN1):c.7806G>A(p.Trp2602Ter) variant causes a stop gained 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
FBN1
NM_000138.5 stop_gained
NM_000138.5 stop_gained
Scores
5
1
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 Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 15-48420700-C-T is Pathogenic according to our data. Variant chr15-48420700-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.7806G>A | p.Trp2602Ter | stop_gained | 63/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.7806G>A | p.Trp2602Ter | stop_gained | 62/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.7806G>A | p.Trp2602Ter | stop_gained | 63/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Marfan syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
Pathogenic, criteria provided, single submitter | research | Centre of Medical Genetics, University of Antwerp | Mar 01, 2021 | PM2, PVS1, PP4 - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 04, 2016 | The p.W2602* pathogenic mutation (also known as c.7806G>A), located in coding exon 62 of the FBN1 gene, results from a G to A substitution at nucleotide position 7806. This changes the amino acid from a tryptophan to a stop codon within coding exon 62. This mutation was detected in one individual with classic Marfan syndrome (Stheneur C, Eur. J. Hum. Genet. 2009 Sep; 17(9):1121-8). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 27, 2012 | c.7806 G>A (TGG>TGA): p.Trp2602Stop in exon 63 of the FBN1 gene (NM_000138.4) The Trp2602Stop mutation in the FBN1 gene has been reported as a de novo mutation in one individual with classic Marfan syndrome (Stheneur C et al., 2009). Trp2602Stop is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense mutations in the FBN1 gene have been reported in association with Marfan syndrome.The variant is found in TAAD panel(s). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -13
Find out detailed SpliceAI scores and Pangolin per-transcript scores at