rs193922204
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_000138.5(FBN1):c.4460-8G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000138.5 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.4460-8G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000316623.10 | |||
FBN1 | NM_001406716.1 | c.4460-8G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.4460-8G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152046Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250992Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135650
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461728Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727180
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152046Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74278
ClinVar
Submissions by phenotype
Marfan syndrome Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Center for Medical Genetics Ghent, University of Ghent | Nov 07, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 07, 2019 | The c.4460-8G>A variant in FBN1 has been reported in at least 3 individuals with Marfan syndrome and segregated with disease in 2 affected individuals from 1 family (Loeys 2001, Pepe 2007, Stheneur 2009). It has also been identified in 0.003% (1/34574) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 36075). This variant is located in the 3' splice region. Computational tools and in vitro splicing assays (Pepe 2007) predict a splicing impact, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PM2, PP3, PS3_Supporting, PS4_Moderate. - |
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 13, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 26, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant negative is a mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0210 - Splice site variant (canonical or non-canonical) proven to affect splicing/expression of the transcript with a known effect on protein structure. This variant has been confirmed by reverse transcriptase PCR (RT-PCR) to activate a cryptic acceptor splice site resulting in an insertion of six intronic nucleotides in exon 36 (c.4459_4460insTTTTAG). The variant results in an in-frame insertion of two amino acids in the protein sequence, p.(Thr1486_Asp1487insValLeu) (PMID: 18087243). (N) 0213 - In-frame insertion in a non-repetitive region that has high conservation. (P) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote). (P) 0507 - Identified variant type is not compatible with in silico predictions of pathogenicity. In-frame insertion not compatible. (N) 0600 - Variant is located in an annotated domain or motif. The insertion occurs between calcium-binding, EGF-like domain 25 and 26, which are normally adjacent to each other (PDB). (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity. In-frame insertion variants in this region have been reported as likely pathogenic and as VUS in ClinVar. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. Five likely pathogenic and two pathogenic entries in ClinVar. Previously reported in multiple patients with Marfan syndrome and ectopia lentis (PMID: 18087243, PMID: 11700157, PMID: 19293843) (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) – Pathogenic, (N) – Neutral, (B) – Benign - |
not specified Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 03, 2017 | - - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 10, 2019 | The c.4460-8G>A intronic variant results from a G to A substitution 8 nucleotides upstream from coding exon 36 in the FBN1 gene. This variant was reported in individuals with features of Marfan syndrome (Loeys B et al. Arch. Intern. Med., 2001 Nov;161:2447-54; Loeys B et al. Hum. Mutat., 2004 Aug;24:140-6; Stheneur C et al. Eur. J. Hum. Genet., 2009 Sep;17:1121-8). In one family, this variant segregated with ectopia lentis in 3 relatives and RT-PCR analysis demonstrated an inframe insertion of 6 nucleotides due to use of a cryptic acceptor site (Pepe G et al. Mol. Vis., 2007 Nov;13:2242-7). Using four different splice site prediction tools, this alteration is predicted by ESEFinder, MaxEnt, and HSF to create a new alternate splice acceptor site, but BDGP does not predict the creation of a non-native acceptor site, nor a deleterious effect on splicing; however, direct evidence is unavailable (Desmet FO et al. Nucleic Acids Res. 2009 May;37:e67). Based on data from gnomAD, the A allele has an overall frequency of approximately <0.001% (1/250992). This nucleotide position is well conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 26, 2021 | Not observed at significant frequency in large population cohorts (Lek et al., 2016); This single nucleotide substitution occurs upstream of the natural splice acceptor site in intron 36 and creates a new cryptic splice acceptor site. Two publications independently reported that cDNA sequence analysis demonstrated the result of this variant to be in-frame insertion of 6 nucleotides into the coding sequence (c.4459_4460insTTTTAG) (Loeys et al., 2001; Pepe et al., 2007).; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 19293843, 18087243, 32679894, 11700157) - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 01, 2024 | This sequence change falls in intron 36 of the FBN1 gene. It does not directly change the encoded amino acid sequence of the FBN1 protein. This variant is present in population databases (rs193922204, gnomAD 0.003%). This variant has been observed in individual(s) with Marfan syndrome (PMID: 11700157, 19293843; Invitae). This variant is also known as IVS35-8G>A. ClinVar contains an entry for this variant (Variation ID: 36075). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Marfan syndrome;C0265287:Acromicric dysplasia;C1858556:MASS syndrome;C1861456:Stiff skin syndrome;C1869115:Weill-Marchesani syndrome 2, dominant;C3280054:Geleophysic dysplasia 2;C3541518:Ectopia lentis 1, isolated, autosomal dominant;C4310796:Progeroid and marfanoid aspect-lipodystrophy syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Nov 11, 2021 | FBN1 NM_000138 exon 37 c.4460-8G>A: This variant has been reported in the literature in at least 3 individuals with features or a clinical suspicion of Marfan syndrome, segregating with disease in 2 affected family members (Loeys 2001 PMID:11700157, Pepe 2007 PMID:18087243, Stheneur 2009 PMID:19293843). This variant is present in 1/33572 Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs193922204). This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:36075). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Additional studies suggest that this variant may activate a cryptic acceptor site and impact the protein (Loeys 2001 PMID:11700157, Pepe 2007 PMID:18087243). However, further studies are needed to understand its impact. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at