15-48411340-AA-TCCT
Position:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000138.5(FBN1):c.8265_8266delinsAGGA(p.Ser2755ArgfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Consequence
FBN1
NM_000138.5 frameshift
NM_000138.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.93
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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 45 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-48411340-AA-TCCT is Pathogenic according to our data. Variant chr15-48411340-AA-TCCT is described in ClinVar as [Pathogenic]. Clinvar id is 179129.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.8265_8266delinsAGGA | p.Ser2755ArgfsTer25 | frameshift_variant | 66/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.8265_8266delinsAGGA | p.Ser2755ArgfsTer25 | frameshift_variant | 65/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.8265_8266delinsAGGA | p.Ser2755ArgfsTer25 | frameshift_variant | 66/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Marfan syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 18, 2013 | The Ser2755fs variant in FBN1 has not been reported in the literature or in larg e population studies. This frameshift variant is predicted to alter the protein? s amino acid sequence beginning at position 2755 and lead to a premature termina tion codon 25 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of function of t he FBN1 gene is an established disease mechanism in Marfan syndrome. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.pa rtners.org/LMM). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at