rs1555405028
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000138.5(FBN1):c.441del(p.Gln147HisfsTer43) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
FBN1
NM_000138.5 frameshift, splice_region
NM_000138.5 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.213
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 18 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 15-48600139-GT-G is Pathogenic according to our data. Variant chr15-48600139-GT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 527202.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.441del | p.Gln147HisfsTer43 | frameshift_variant, splice_region_variant | 5/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.441del | p.Gln147HisfsTer43 | frameshift_variant, splice_region_variant | 4/65 | ||
FBN1 | NM_001406717.1 | c.441del | p.Gln147HisfsTer43 | frameshift_variant, splice_region_variant | 5/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.441del | p.Gln147HisfsTer43 | frameshift_variant, splice_region_variant | 5/66 | 1 | NM_000138.5 | P1 | |
FBN1 | ENST00000559133.6 | c.441del | p.Gln147HisfsTer43 | frameshift_variant, splice_region_variant, NMD_transcript_variant | 5/67 | 1 | |||
FBN1 | ENST00000674301.2 | c.441del | p.Gln147HisfsTer43 | frameshift_variant, splice_region_variant, NMD_transcript_variant | 5/68 | ||||
FBN1 | ENST00000537463.6 | c.441del | p.Gln147HisfsTer43 | frameshift_variant, splice_region_variant, NMD_transcript_variant | 5/31 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
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 | Nov 05, 2018 | Variant summary: FBN1 c.441delA (p.Gln147HisfsX43) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.493C>T, p.Arg165X; c.643C>T, p.Arg215X; c.1010dupA, p.Tyr337X). The variant was absent in 245954 control chromosomes (gnomAD). The variant, c.441delA, has been reported in the literature in one individual affected with Marfan Syndrome (Vatti_2017). This report does not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2022 | This sequence change creates a premature translational stop signal (p.Gln147Hisfs*43) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 28941062). This variant is also known as c.441delA, p.Gln147*. ClinVar contains an entry for this variant (Variation ID: 527202). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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Calibrated prediction
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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