rs193922196
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The ENST00000316623.10(FBN1):c.3082+8del variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00061 in 1,612,022 control chromosomes in the GnomAD database, including 4 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0033 ( 2 hom., cov: 31)
Exomes 𝑓: 0.00033 ( 2 hom. )
Consequence
FBN1
ENST00000316623.10 splice_region, intron
ENST00000316623.10 splice_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.363
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 -16 ACMG points.
BP6
Variant 15-48489842-AC-A is Benign according to our data. Variant chr15-48489842-AC-A is described in ClinVar as [Likely_benign]. Clinvar id is 36062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48489842-AC-A is described in Lovd as [Benign]. Variant chr15-48489842-AC-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00329 (501/152326) while in subpopulation AFR AF= 0.0115 (480/41576). AF 95% confidence interval is 0.0107. There are 2 homozygotes in gnomad4. There are 223 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 501 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.3082+8del | splice_region_variant, intron_variant | ENST00000316623.10 | NP_000129.3 | |||
FBN1 | NM_001406716.1 | c.3082+8del | splice_region_variant, intron_variant | NP_001393645.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.3082+8del | splice_region_variant, intron_variant | 1 | NM_000138.5 | ENSP00000325527 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00328 AC: 499AN: 152208Hom.: 2 Cov.: 31
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GnomAD3 exomes AF: 0.000851 AC: 213AN: 250156Hom.: 1 AF XY: 0.000561 AC XY: 76AN XY: 135396
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GnomAD4 exome AF: 0.000330 AC: 482AN: 1459696Hom.: 2 Cov.: 31 AF XY: 0.000249 AC XY: 181AN XY: 726290
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GnomAD4 genome AF: 0.00329 AC: 501AN: 152326Hom.: 2 Cov.: 31 AF XY: 0.00299 AC XY: 223AN XY: 74496
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Uncertain:1Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 22, 2011 | 3082+8delG in intron 24 of FBN1: This variant has not been previously reported, but is not expected to be of clinical significance because it is not located in the conserved region of the splicing consensus sequence. - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 31, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 06, 2015 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Familial thoracic aortic aneurysm and aortic dissection Benign:3
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 05, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 02, 2017 | This alteration is classified as 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. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 18, 2014 | The variant is found in TAAD panel(s). - |
Marfan syndrome Uncertain:1Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Center for Medical Genetics Ghent, University of Ghent | Nov 07, 2017 | - - |
Benign, no assertion criteria provided | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 17, 2014 | - - |
not provided Benign:1
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
FBN1-related disorder Benign:1
Benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 17, 2019 | This variant is classified as 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
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | - - |
Computational scores
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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