rs140648
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The ENST00000316623.10(FBN1):c.3963A>G(p.Thr1321=) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T1321T) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 33)
Consequence
FBN1
ENST00000316623.10 splice_region, synonymous
ENST00000316623.10 splice_region, synonymous
Scores
2
Splicing: ADA: 0.9381
1
1
Clinical Significance
Conservation
PhyloP100: 6.21
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.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-48481656-T-C is Pathogenic according to our data. Variant chr15-48481656-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.3963A>G | p.Thr1321= | splice_region_variant, synonymous_variant | 32/66 | ENST00000316623.10 | NP_000129.3 | |
FBN1 | NM_001406716.1 | c.3963A>G | p.Thr1321= | splice_region_variant, synonymous_variant | 31/65 | NP_001393645.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.3963A>G | p.Thr1321= | splice_region_variant, synonymous_variant | 32/66 | 1 | NM_000138.5 | ENSP00000325527 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Marfan syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | research | Centre of Medical Genetics, University of Antwerp | Mar 01, 2021 | PM2, PS1, PP4 - |
Likely pathogenic, no assertion criteria provided | clinical testing | Center for Medical Genetics Ghent, University of Ghent | Nov 07, 2017 | - - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 17, 2015 | The c.3963A>G variant (also known as p.T1321T), located in coding exon 31, results from an A to G substitution at nucleotide position 3963 of the FBN1 gene. This nucleotide substitution does not change the amino acid at codon 1321. In one study, this substitution was found to alter the second to last nucleotide of codingexon31 and resulted inexonskipping and abnormal splicing detected byRT-PCRanalysis of total RNA isolated from cultured fibroblasts (Liu et al.Genet Test. 1997-1998;1(4):237-242).In another study, this variant was reported in a patient with predominantectopialentisand other features ofMarfansyndrome (ComeglioP et al.Br JOphthalmol. 2002: 86(12); 1359-1362).This sequence variation was also reported in a patient and his similarly affected daughter, though the authors suggested the possibility that an additional mutation may exist that was not detected byheteroduplexanalysis (HallidayD et al.Hum Genet. 1999; 105(6): 587-597). It was also detected inan individual presented with skeletal system involved, aortic dilatation and family history ofectopia lentis but did not fulfillGhentcriteria (Turner CL et al, Am. J. Med. Genet. A 2009 Feb;149A(2):161-70).This variant was previously reported in the SNPDatabase as rs140648. It<span style="font-family:arial,sans-serif; font-size:10pt">was not reported in population based cohorts in the following databases: NHLBIExomeSequencing Project (ESP)and 1000 Genomes Project. In the ESP, this variant was not observed in 6494<span style="font-family:arial,sans-serif; font-size:10pt">samples (12988 alleles) with coverage at this position.<span style="line-height:13.8667px">Using theBDGP<span style="line-height:13.8667px">andESEfinder<span style="line-height:13.8667px">splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable.<span style="font-family:arial,sans-serif; font-size:10pt">Another algorithm also predicted the variant to cause aberrant splicing (Sahashi<span style="line-height:1.6">K et al<span style="line-height:1.6">, <em style="line-height:1.6">Nucleic Acids Res<span style="line-height:1.6">. 2007<span style="line-height:1.6">; 35(18):5995-6003).Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 06, 2023 | This sequence change affects codon 1321 of the FBN1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FBN1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of FBN1-related conditions (PMID: 10464652, 10647894, 12446365, 17657824, 19161152, 35058154). ClinVar contains an entry for this variant (Variation ID: 520237). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 5
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at