rs1555398753
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000138.5(FBN1):c.3061_3082+172del(p.Asn1021fs) variant causes a frameshift, splice donor, splice region, intron 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 (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Consequence
FBN1
NM_000138.5 frameshift, splice_donor, splice_region, intron
NM_000138.5 frameshift, splice_donor, splice_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.790
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 15-48489678-GGACCAAACAGTTAAAAACAAAAAGTTCATACTTTTCTAAACAAAGATAATTATATAATTCAGAAAGCAAAAAGTCCATGCTGGGATGATCAAGTAGAGTGCTGAGATCATGAAAATGCATCCTATTTGTCTAAAAAGGGAGGCAATTGGCCATGGAAAACGTAACATTGTACCTTTGAAGAAAGGCTTTCCATT-G is Pathogenic according to our data. Variant chr15-48489678-GGACCAAACAGTTAAAAACAAAAAGTTCATACTTTTCTAAACAAAGATAATTATATAATTCAGAAAGCAAAAAGTCCATGCTGGGATGATCAAGTAGAGTGCTGAGATCATGAAAATGCATCCTATTTGTCTAAAAAGGGAGGCAATTGGCCATGGAAAACGTAACATTGTACCTTTGAAGAAAGGCTTTCCATT-G is described in ClinVar as [Pathogenic]. Clinvar id is 457187.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.3061_3082+172del | p.Asn1021fs | frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant | 25/66 | ENST00000316623.10 | NP_000129.3 | |
FBN1 | NM_001406716.1 | c.3061_3082+172del | p.Asn1021fs | frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant | 24/65 | NP_001393645.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.3061_3082+172del | p.Asn1021fs | frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant | 25/66 | 1 | NM_000138.5 | ENSP00000325527.5 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 13, 2017 | This is a large deletion affecting part of exon 25 and extending into intron 25, with one breakpoint at position c.3061 and the other breakpoint at position c.3082+172. This sequence change creates a premature translational stop signal (p.Asn1021Ilefs*7) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FBN1-related disease. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at