rs1555401686
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000138.5(FBN1):c.650G>A(p.Trp217Ter) 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
FBN1
NM_000138.5 stop_gained
NM_000138.5 stop_gained
Scores
4
2
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 12 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 15-48537697-C-T is Pathogenic according to our data. Variant chr15-48537697-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 519741.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.650G>A | p.Trp217Ter | stop_gained | 7/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.650G>A | p.Trp217Ter | stop_gained | 6/65 | ||
FBN1 | NM_001406717.1 | c.650G>A | p.Trp217Ter | stop_gained | 7/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.650G>A | p.Trp217Ter | stop_gained | 7/66 | 1 | NM_000138.5 | P1 | |
FBN1 | ENST00000559133.6 | c.650G>A | p.Trp217Ter | stop_gained, NMD_transcript_variant | 7/67 | 1 | |||
FBN1 | ENST00000674301.2 | c.650G>A | p.Trp217Ter | stop_gained, NMD_transcript_variant | 7/68 | ||||
FBN1 | ENST00000537463.6 | c.636+14G>A | intron_variant, NMD_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 11, 2016 | The p.W217* pathogenic mutation (also known as c.650G>A), located in coding exon 6 of the FBN1 gene, results from a G to A substitution at nucleotide position 650. This changes the amino acid from a tryptophan to a stop codon within coding exon 6. This alteration, as well as a different nucleotide change (c.651G>A) resulting in the same amino acid alteration, have been reported in individuals with some features consistent with Marfan syndrome (Baudhuin LM et al. J Hum Genet. 2015;60:241-52; Magyar I et al. Hum Mutat. 2009;30:1355-64). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, 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
Uncertain
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
Find out detailed SpliceAI scores and Pangolin per-transcript scores at