chr15-48489850-C-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Moderate
The NM_000138.5(FBN1):c.3082+1G>C variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 31)
Consequence
FBN1
NM_000138.5 splice_donor
NM_000138.5 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.90
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 Pathogenic. Variant got 10 ACMG points.
PVS1
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.026346333 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 15-48489850-C-G is Pathogenic according to our data. Variant chr15-48489850-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 263975.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.3082+1G>C | splice_donor_variant | ENST00000316623.10 | |||
FBN1 | NM_001406716.1 | c.3082+1G>C | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.3082+1G>C | splice_donor_variant | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 26, 2015 | The c.3082+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 24 of the FBN1 gene. Another splicing pathogenic mutation has been described at the same nucleotide position (c.3082+1G>T). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native donor splice site; however, direct evidence is unavailable. In addition to the clinical data presented in the literature, since alterations that disrupt the canonical splice donor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -6
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at