rs1555396789
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM4_SupportingPP5
The NM_000138.5(FBN1):c.5076_5078del(p.Arg1692del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1692R) has been classified as Likely benign.
Frequency
Consequence
NM_000138.5 inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.5076_5078del | p.Arg1692del | inframe_deletion | 42/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.5076_5078del | p.Arg1692del | inframe_deletion | 41/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.5076_5078del | p.Arg1692del | inframe_deletion | 42/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461724Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727170
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 19, 2022 | Not observed in large population cohorts (gnomAD); In-frame deletion of one arginine amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17657824, 34008892, 32679894, 27146836, 33844962) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Jul 03, 2017 | - - |
Marfan syndrome Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Center for Medical Genetics Ghent, University of Ghent | Nov 07, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 01, 2021 | PM1, PM2, PM4, PP3 - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jul 02, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 30, 2019 | The c.5076_5078delAAG variant (also known as p.R1692del) is located in coding exon 41 of the FBN1 gene. This variant results from an in-frame AAG deletion at nucleotide positions 5076 to 5078. This results in the in-frame deletion of an arginine at codon 1692, and is located in the TGFB#05 domain. This variant (also described as c.5074_5076delAGA) was first reported in a child with ectopia lentis and no other clinical findings of Marfan syndrome (MFS) at the time of evaluation (Comeglio P et al. Hum. Mutat., 2007 Sep;28:928). This variant has also been detected in an individual meeting clinical diagnostic criteria for MFS, as well as in his asymptomatic father (Poninska JK et al. J Transl Med, 2016 05;14:115). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2023 | This variant, c.5076_5078del, results in the deletion of 1 amino acid(s) of the FBN1 protein (p.Arg1692del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Marfan syndrome (PMID: 17657824, 27146836, 32679894; Invitae). ClinVar contains an entry for this variant (Variation ID: 520496). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at