rs112269822
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP2PP3BS2
The NM_000138.5(FBN1):āc.1640T>Cā(p.Ile547Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I547V) 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.1640T>C | p.Ile547Thr | missense_variant | 14/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.1640T>C | p.Ile547Thr | missense_variant | 13/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.1640T>C | p.Ile547Thr | missense_variant | 14/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251286Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135806
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461198Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10AN XY: 726912
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Marfan syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 15, 2023 | This missense variant replaces isoleucine with threonine at codon 547 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with FBN1-related disorders in the literature. This variant has been identified in 2/251286 chromosomes 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. - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 10, 2018 | 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 has not been reported in the literature in individuals with FBN1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 547 of the FBN1 protein (p.Ile547Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at