rs1555397163
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PP5_Moderate
The NM_000138.5(FBN1):c.4640_4641del(p.Thr1547SerfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
FBN1
NM_000138.5 frameshift
NM_000138.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.61
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 10 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 15-48468043-CTG-C is Pathogenic according to our data. Variant chr15-48468043-CTG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495613.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.4640_4641del | p.Thr1547SerfsTer5 | frameshift_variant | 38/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.4640_4641del | p.Thr1547SerfsTer5 | frameshift_variant | 37/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.4640_4641del | p.Thr1547SerfsTer5 | frameshift_variant | 38/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
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
Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 22, 2016 | Variant summary: This c.4640_4641delCA variant causes a frameshift, which alters the proteins amino acid sequence beginning at position 1547 and leads to a premature termination codon four amino acids downstream. It is predicted to cause a truncated or absent protein product. Mutation taster predicts this variant to be disease-causing. The variant was not observed in the large and broad cohorts of the ExAC project or ESP. The variant of interest was reported in one MFS patient with positive family history (Baudhuin_2015). Truncations downstream of this position have been classified as disease variants by our laboratory (Such as R1596X and R1644X). Considering all, this variant has been classified as Likely Pathogenic until additional information becomes available. - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at