rs363802
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2
The ENST00000316623.10(FBN1):c.6052G>A(p.Val2018Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,613,488 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2018A) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000316623.10 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.6052G>A | p.Val2018Ile | missense_variant | 50/66 | ENST00000316623.10 | NP_000129.3 | |
FBN1 | NM_001406716.1 | c.6052G>A | p.Val2018Ile | missense_variant | 49/65 | NP_001393645.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.6052G>A | p.Val2018Ile | missense_variant | 50/66 | 1 | NM_000138.5 | ENSP00000325527 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152208Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000188 AC: 47AN: 250566Hom.: 0 AF XY: 0.000170 AC XY: 23AN XY: 135408
GnomAD4 exome AF: 0.0000417 AC: 61AN: 1461162Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28AN XY: 726908
GnomAD4 genome AF: 0.0000919 AC: 14AN: 152326Hom.: 1 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74476
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 12, 2018 | The FBN1 c.6052G>A, p.Val2018Ile variant (rs363802) has not been reported in the medical literature, but is listed in ClinVar (Variation ID: 200073). It is observed in the Genome Aggregation Database general population database at a frequency of 0.14 percent in the Latino population (48/34352 alleles). The valine at residue 2018 is highly conserved, but computational algorithms (Align GVGD, PolyPhen-2, SIFT) predict that the variant has minimal impact on the protein. Due to the limited information regarding this variant, its clinical significance could not be determined with certainty. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 29, 2021 | This variant is associated with the following publications: (PMID: 27535533, 11875032, 12938084) - |
Familial thoracic aortic aneurysm and aortic dissection Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 23, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 07, 2020 | 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. - |
Marfan syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | May 31, 2019 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 31, 2021 | Variant summary: FBN1 c.6052G>A (p.Val2018Ile) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 250566 control chromosomes, predominantly at a frequency of 0.0013 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.6052G>A in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign. - |
FBN1-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 10, 2024 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 27, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at