rs1555405039
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate
The NM_000138.5(FBN1):c.408C>G(p.Cys136Trp) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★).
Frequency
Consequence
NM_000138.5 missense
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.408C>G | p.Cys136Trp | missense_variant | Exon 5 of 66 | ENST00000316623.10 | NP_000129.3 | |
FBN1 | NM_001406716.1 | c.408C>G | p.Cys136Trp | missense_variant | Exon 4 of 65 | NP_001393645.1 | ||
FBN1 | NM_001406717.1 | c.408C>G | p.Cys136Trp | missense_variant | Exon 5 of 9 | NP_001393646.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.408C>G | p.Cys136Trp | missense_variant | Exon 5 of 66 | 1 | NM_000138.5 | ENSP00000325527.5 | ||
FBN1 | ENST00000559133.6 | n.408C>G | non_coding_transcript_exon_variant | Exon 5 of 67 | 1 | ENSP00000453958.2 | ||||
FBN1 | ENST00000537463.6 | n.408C>G | non_coding_transcript_exon_variant | Exon 5 of 31 | 5 | ENSP00000440294.2 | ||||
FBN1 | ENST00000674301.2 | n.408C>G | non_coding_transcript_exon_variant | Exon 5 of 68 | ENSP00000501333.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
The p.C136W variant (also known as c.408C>G), located in coding exon 4 of the FBN1 gene, results from a C to G substitution at nucleotide position 408. The cysteine at codon 136 is replaced by tryptophan, an amino acid with highly dissimilar properties. Alterations affecting the same amino acid, p.C136S (c.406T>A), p.C136R (c.406T>C) and p.C136F(c.407G>T) have been reported in association with Marfan syndrome (Attanasio M et al, Clin. Genet. 2008 Jul; 74(1):39-46; Groth KA et al. Genet. Med., 2017 07;19:772-777). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). Based on internal structural assessment, this alteration eliminates a structurally critical disulfide in the structurally sensitive EGF-like domain #02. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at