rs563973570
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The NM_000138.5(FBN1):c.6998-33del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000871 in 1,599,060 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..
Frequency
Genomes: 𝑓 0.00077 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00088 ( 1 hom. )
Consequence
FBN1
NM_000138.5 intron
NM_000138.5 intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -1.22
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 15-48427805-TC-T is Benign according to our data. Variant chr15-48427805-TC-T is described in ClinVar as [Likely_benign]. Clinvar id is 495642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000775 (118/152266) while in subpopulation SAS AF= 0.00249 (12/4824). AF 95% confidence interval is 0.00144. There are 1 homozygotes in gnomad4. There are 64 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 118 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.6998-33del | intron_variant | ENST00000316623.10 | |||
FBN1 | NM_001406716.1 | c.6998-33del | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.6998-33del | intron_variant | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000776 AC: 118AN: 152148Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.000992 AC: 241AN: 242840Hom.: 0 AF XY: 0.00115 AC XY: 151AN XY: 131056
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GnomAD4 exome AF: 0.000881 AC: 1274AN: 1446794Hom.: 1 Cov.: 28 AF XY: 0.000921 AC XY: 663AN XY: 720100
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GnomAD4 genome AF: 0.000775 AC: 118AN: 152266Hom.: 1 Cov.: 33 AF XY: 0.000860 AC XY: 64AN XY: 74452
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | FBN1: BS1 - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 15, 2016 | Variant summary: The FBN1 c.6998-33delG variant involves the alteration of a non-conserved intronic nucleotide. Mutation Taster tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 140/105650 control chromosomes at a frequency of 0.0013251, which is approximately 12 times the estimated maximal expected allele frequency of a pathogenic FBN1 variant (0.0001125), suggesting this variant is likely a benign polymorphism. It has also been reported as a polymorphism in literature (Korkko_2002) and co-occurs with a potentially pathogenic variant p.Cys186Arg in an internal sample. Taken together, this variant is classified as Benign. - |
FBN1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 28, 2021 | 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). - |
Computational scores
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La Branchor
BranchPoint Hunter
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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