rs397515777
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP2BP4
The NM_000138.5(FBN1):c.2519C>T(p.Pro840Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P840Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.2519C>T | p.Pro840Leu | missense_variant | 21/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.2519C>T | p.Pro840Leu | missense_variant | 20/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.2519C>T | p.Pro840Leu | missense_variant | 21/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461678Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727144
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 26, 2012 | The Pro840Leu variant (FBN1) has not been reported in the literature nor previou sly identified by our laboratory. This amino acid residue is not conserved acro ss mammals (orangutan has an alanine at this position) suggesting a change at th is position could be tolerated and computational analyses (biochemical amino aci d properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide stron g support for or against an impact to the protein. However, this information is not predictive enough to rule out pathogenicity. Therefore, additional informat ion is needed to fully assess the clinical significance of the Pro840Leu variant . - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at