rs397515757

Positions:

• chr15-48515382-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000138.5(FBN1):​c.1468+5G>A variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FBN1 NM_000138.5 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 5.83

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]

FBN1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 4: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai [when BayesDel_noAF, Dann was below the threshold]
• PP5: Variant 15-48515382-C-T is Pathogenic according to our data. Variant chr15-48515382-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42284.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.1468+5G>A		splice_region_variant, intron_variant		ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.1468+5G>A		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.1468+5G>A		splice_region_variant, intron_variant		1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461588 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727104

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 23, 2017	The c.1468+5G>A variant in FBN1 has been reported in 9 individuals with clinical features of Marfan syndrome (Aalberts 2014, Baetens 2011, Comeglio 2007, Liu 19 97-1998, LMM data). It has not been identified in large population studies. In a ddition, this variant has segregated with disease in 5 affected individuals from one family tested by our laboratory. The c.1468+5G>A variant is located in the 5' splice region and RNA studies have revealed this splice site variant leads to abnormal splicing and exon skipping in FBN1 (Aalberts 2014, Ogawa 2011, Liu 199 7-1998), resulting in an abnormal or absent protein. Heterozygous loss of functi on of the FBN1 gene is an established disease mechanism in Marfan syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosoma l dominant Marfan syndrome based on its recurrence in multiple affected individu als, segregation in families, extremely low allele frequency in the general popu lation, and functional impact on splicing. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Dec 13, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Blueprint Genetics	May 16, 2014	- -
Likely pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PS1, PP4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 11, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 07, 2020	The c.1468+5G>A intronic pathogenic mutation (also known as c.IVS11+5G>A) results from a G to A substitution 5 nucleotides after coding exon 11 in the FBN1 gene. This mutation has been detected in individuals with classical Marfan syndrome and in individuals with Marfan-related features, including isolated ectopia lentis, thoracic aortic aneurysm and dissections, and/or skeletal findings (Liu WO et al. Genet Test. 1997-1998;1:237-42; Comeglio P et al. Hum Mutat. 2007;28:928; Aalberts JJ et al. Gene, 2014 Jan;534:40-3; Weerakkody R et al. Genet Med, 2018 11;20:1414-1422; Mannucci L et al. Clin Chim Acta, 2020 Feb;501:154-164). RNA studies found that a cryptic splice donor site within exon 11 can become activated in the presence of this alteration, which leads to loss of a critical region of the protein (Ogawa N et al. Am J Cardiol. 2011;108:1801-7). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration may weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, no assertion criteria provided	research	Centre for Genomic and Experimental Medicine, University of Edinburgh	-	- -

Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 13, 2023

Variant summary: FBN1 c.1468+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict abolishing and two predict severe weakening of the 5' splice site. RNA studies found that a cryptic donor site in exon 11 became activated, resulting in loss of critical region (Ogawa_2011). The variant was absent in 251358 control chromosomes. c.1468+5G>A has been reported in the literature in multiple individuals affected with Marfan Syndrome (Example: Baetens_2011, Liu_1997, Hogwarth_2007, Ogawa_2011, Comeglio_2007 etc.). These data indicate that the variant is very likely to be associated with disease. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=9) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 24, 2022

Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Published functional studies demonstrate that c.1468+5 G>A destroys the natural splice donor site and results in abnormal splicing (Ogawa et al., 2011); This variant is associated with the following publications: (PMID: 29543232, 31730815, 25525159, 17657824, 19949477, 19339519, 25907466, 24161884, 21542060, 17627385, 11702223, 27085269, 11933199, 33726816, 10464652, 25101912, 21907952, 34498425) -

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

This sequence change falls in intron 12 of the FBN1 gene. It does not directly change the encoded amino acid sequence of the FBN1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Marfan syndrome (PMID: 10464652, 17627385, 17657824, 25101912, 25907466). In at least one individual the variant was observed to be de novo. This variant is also known as IVS11+5G>A. ClinVar contains an entry for this variant (Variation ID: 42284). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in creation of a new donor splice site and introduces a premature termination codon (PMID: 21907952). The resulting mRNA is expected to undergo nonsense-mediated decay. 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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	33
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.64		Position offset: -13
DS_DL_spliceai		0.38		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397515757; hg19: chr15-48807579;