rs764224168
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP2PP3
The NM_000138.5(FBN1):c.370A>G(p.Met124Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,766 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M124I) 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.370A>G | p.Met124Val | missense_variant | 5/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.370A>G | p.Met124Val | missense_variant | 4/65 | ||
FBN1 | NM_001406717.1 | c.370A>G | p.Met124Val | missense_variant | 5/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.370A>G | p.Met124Val | missense_variant | 5/66 | 1 | NM_000138.5 | P1 | |
FBN1 | ENST00000559133.6 | c.370A>G | p.Met124Val | missense_variant, NMD_transcript_variant | 5/67 | 1 | |||
FBN1 | ENST00000674301.2 | c.370A>G | p.Met124Val | missense_variant, NMD_transcript_variant | 5/68 | ||||
FBN1 | ENST00000537463.6 | c.370A>G | p.Met124Val | missense_variant, NMD_transcript_variant | 5/31 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250938Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135582
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461634Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727144
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74308
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 | Jul 26, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 Marfan proband and an additional individual who died suddently (thesis in spanish - https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=10&cad=rja&uact=8&ved=0ahUKEwiErr6GwYfMAhWluoMKHUGVA0sQFghCMAk&url=http%3A%2F%2Frua.ua.es%2Fdspace%2Fbitstream%2F10045%2F47409%2F1%2Ftesis_sonia_santillan_garzon.pdf&usg=AFQjCNFIEBTg3Y7AD4w_s01zJG7D0gJDdQ&sig2=BpN6DJWBcJGCzKnmEEVyGQ&bvm=bv.119028448,d.d2s) - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 13, 2021 | This sequence change replaces methionine with valine at codon 124 of the FBN1 protein (p.Met124Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs764224168, ExAC 0.009%). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 21932315). ClinVar contains an entry for this variant (Variation ID: 402851). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at