rs587782948
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000138.5(FBN1):c.8521G>T(p.Glu2841Ter) variant causes a stop gained 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 (★★).
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: 5.90
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 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 15-48411085-C-A is Pathogenic according to our data. Variant chr15-48411085-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 155795.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.8521G>T | p.Glu2841Ter | stop_gained | 66/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.8521G>T | p.Glu2841Ter | stop_gained | 65/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.8521G>T | p.Glu2841Ter | stop_gained | 66/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
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
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 08, 2018 | The E2841X likely pathogenic variant in the FBN1 gene has been reported in a Japanese individual evaluated for suspected Marfan syndrome (Ogawa et al., 2011); however, no specific clinical details were provided. The E2841X variant is located in the last exon of the FBN1 gene and is predicted to result in an abnormal, truncated protein product. If the protein produced is stable, the expected result is loss of the last 31 amino acid residues. Other downstream nonsense and frameshift variants in the FBN1 gene have been reported in Human Gene Mutation Database in association with Marfan syndrome and TAAD (Stenson et al., 2014). Furthermore, the E2841X variant is not observed in large population cohorts (Lek et al., 2016). - |
Marfan syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Blueprint Genetics | Jan 29, 2014 | - - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 05, 2023 | The p.E2841* pathogenic mutation (also known as c.8521G>T), located in coding exon 65 of the FBN1 gene, results from a G to T substitution at nucleotide position 8521. This changes the amino acid from a glutamic acid to a stop codon within coding exon 65. This alteration occurs at the 3' terminus of theFBN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 31 amino acids (1%) of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been previously reported in a cohort of patients with suspected or confirmed Marfan syndrome (Ogawa N et al. Am. J. Cardiol. 2011;108:1801-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
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
D
Vest4
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