rs193922231
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Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2
The NM_000138.5(FBN1):c.7230C>T(p.His2410=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000788 in 1,610,682 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000084 ( 0 hom. )
Consequence
FBN1
NM_000138.5 synonymous
NM_000138.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.472
Genes affected
FBN1 (HGNC:3603): (fibrillin 1) This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -15 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.44).
BP6
?
Variant 15-48425839-G-A is Benign according to our data. Variant chr15-48425839-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48425839-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-0.472 with no splicing effect.
BS2
?
High AC in GnomAd4 at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.7230C>T | p.His2410= | synonymous_variant | 59/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.7230C>T | p.His2410= | synonymous_variant | 58/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.7230C>T | p.His2410= | synonymous_variant | 59/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152034Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000717 AC: 18AN: 251166Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135748
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GnomAD4 exome AF: 0.0000836 AC: 122AN: 1458648Hom.: 0 Cov.: 29 AF XY: 0.000106 AC XY: 77AN XY: 725864
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GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152034Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74234
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ClinVar
Significance: Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 03, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 30, 2023 | 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 provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 11, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 06, 2021 | - - |
Marfan syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 04, 2018 | Variant summary: FBN1 c.7230C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.3e-05 in 245938 control chromosomes, predominantly within the European (Non-Finnish) subpopulation at a frequency of 0.00013 in the gnomAD database. The observed variant frequency within European (Non-Finnish) control individuals in the gnomAD database is approximately 1.16 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), suggesting that the variant is a benign polymorphism. To our knowledge, no occurrence of c.7230C>T in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at