15-48470756-T-C
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong
The NM_000138.5(FBN1):āc.4337A>Gā(p.Asp1446Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D1446N) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000138.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.4337A>G | p.Asp1446Gly | missense_variant, splice_region_variant | 36/66 | ENST00000316623.10 | NP_000129.3 | |
FBN1 | NM_001406716.1 | c.4337A>G | p.Asp1446Gly | missense_variant, splice_region_variant | 35/65 | NP_001393645.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.4337A>G | p.Asp1446Gly | missense_variant, splice_region_variant | 36/66 | 1 | NM_000138.5 | ENSP00000325527 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461820Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727210
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Marfan syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | May 22, 2022 | This variant has been reported in the literature in two individuals with aortic disease (Baudhuin 2015 PMID: 25652356; Li 2021 PMID: 33824467). This variant is not present in large control databases but is present in ClinVar (Variation ID: 924199). Evolutionary conservation and computational predictive tools suggest that this variant impacts the protein. This variant is located within the consensus binding sequence in a calcium-binding epidermal growth factor (cbEGF)-like domain and may impair protein folding or stabilization (Jensen 2005 PMID: 15649891). Other variants at this same position have been reported in association with Marfan syndrome or aortic disease (p.Asp1446Val, p.Asp1446Asn). In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 23, 2019 | This missense variant replaces the conserved aspartic acid with glycine at codon 1446 in the calcium-binding EGF-like motif 25 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual suspected of having Marfan syndrome (PMID: 25652356). This proband showed cardiovascular involvement with unknown Ghent criteria and no family history of Marfan syndrome. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Isolated thoracic aortic aneurysm Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Department of Vascular Biology, Beijing Anzhen Hospital | Sep 01, 2018 | - - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 13, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Asp1446 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 25652356, 25907466), which suggests that this may be a clinically significant amino acid residue. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 924199). This missense change has been observed in individuals with clinical features of Marfan syndrome and/or FBN1-related conditions (PMID: 25652356, 33824467; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1446 of the FBN1 protein (p.Asp1446Gly). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at