chr15-48468534-T-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_000138.5(FBN1):c.4460A>C(p.Asp1487Ala) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1487N) has been classified as Pathogenic.
Frequency
Consequence
NM_000138.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.4460A>C | p.Asp1487Ala | missense_variant, splice_region_variant | 37/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.4460A>C | p.Asp1487Ala | missense_variant, splice_region_variant | 36/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.4460A>C | p.Asp1487Ala | missense_variant, splice_region_variant | 37/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Marfan syndrome Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Center for Medical Genetics Ghent, University of Ghent | Nov 07, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | research | Centre of Medical Genetics, University of Antwerp | Mar 01, 2021 | PM2, PS6, PP4 - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2022 | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 1487 of the FBN1 protein (p.Asp1487Ala). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 21542060; Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asp148 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30838813; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 549234). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 21, 2022 | Reported in a patient with Marfan syndrome in published literature (Baetens et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20591885, 21542060) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at