rs139968089
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4BP6BS1BS2
The NM_000138.5(FBN1):c.1265G>A(p.Gly422Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G422G) has been classified as Likely benign.
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.1265G>A | p.Gly422Glu | missense_variant | 11/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.1265G>A | p.Gly422Glu | missense_variant | 10/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.1265G>A | p.Gly422Glu | missense_variant | 11/66 | 1 | NM_000138.5 | P1 | |
FBN1 | ENST00000559133.6 | c.1265G>A | p.Gly422Glu | missense_variant, NMD_transcript_variant | 11/67 | 1 | |||
FBN1 | ENST00000674301.2 | c.1265G>A | p.Gly422Glu | missense_variant, NMD_transcript_variant | 11/68 | ||||
FBN1 | ENST00000537463.6 | c.636+21466G>A | intron_variant, NMD_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000336 AC: 51AN: 151584Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251246Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135784
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461740Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8AN XY: 727188
GnomAD4 genome ? AF: 0.000336 AC: 51AN: 151702Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21AN XY: 74116
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 13, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 31, 2018 | The G422E variant of uncertain significance in the FBN1 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, G422E does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003). Furthermore, this variant is observed in 23/23,998 (0.1%) African alleles in large population cohorts (Lek et al., 2016), indicating it may be a rare benign variant in this population. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 04, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 29, 2019 | The FBN1 c.1265G>A; p.Gly422Glu variant (rs139968089), to our knowledge, is not reported in the medical literature. The variant is reported as a variant of uncertain significance in the ClinVar database (Variation ID: 200178) and is found in the African population with an allele frequency of 0.09% (23/24,922 alleles) in the Genome Aggregation Database. The glycine at codon 422 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Gly422Glu variant is uncertain at this time. - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | FBN1: BS1 - |
Familial thoracic aortic aneurysm and aortic dissection Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 19, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 29, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 16, 2019 | Variant summary: FBN1 c.1265G>A (p.Gly422Glu) results in a non-conservative amino acid change in the encoded protein sequence. It is located outside of known functional domains such as EGF-like- or TB domains (InterPro). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-05 in 282580 control chromosomes, predominantly at a frequency of 0.00092 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Aortopathy phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.1265G>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 14, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at