chr15-48428485-T-C

Position:

• chr15-48428485-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000138.5(FBN1):​c.6872-14A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3
• Conservation: PhyloP100: -0.0510

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 15-48428485-T-C is Pathogenic according to our data. Variant chr15-48428485-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 418201.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=2, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.6872-14A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.6872-14A>G		splice_polypyrimidine_tract_variant, intron_variant			NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.6872-14A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Marfan syndrome Pathogenic:1 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change in FBN1 is an intronic variant located in intron 56. This variant is absent from gnomAD v2.1 and v3.1. This variant has been reported in at least two probands with a clinical diagnosis of Marfan syndrome and a proband with thoracic aortic aneurysm and aortic dissection (PMID: 25907466, 29510914; Royal Melbourne Hospital). It has also been identified as a de novo occurrence with unconfirmed parental relationships in an individual with Marfan syndrome (SCV000787274.1). The results from multiple in silico splicing predictors (SpliceAI, MaxEntScan, NNSplice) indicate that this variant may impact splicing by disrupting the acceptor splice site of intron 56 of FBN1 by gain of a de novo acceptor site upstream. This prediction is confirmed by RT-PCR of patient RNA. The assay demonstrated that the variant impacts splicing by use of a cryptic acceptor (unable to determine if complete/partial mis-splicing) within intron 56 (r.6871_6872ins[6872-13_6872-1]) resulting in a frameshift (p.Asp2291Valfs*6; RNA Diagnostics Kid's Neuroscience Centre) leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a LIKELY PATHOGENIC. Following criteria are met: PS3_Moderate, PS4_Moderate, PM2_Supporting, PM6_Supporting, PP3. -
Uncertain significance, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PP3, PP1, PP4 -
Uncertain significance, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 27, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 29510914, 35058154, 25907466) -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2018

The c.6872-14A>G intronic pathogenic mutation results from an A to G substitution 14 nucleotides upstream from coding exon 56 in the FBN1 gene. This alteration has been detected in multiple patients with Marfan syndrome (MFS) or MFS-related phenotypes and was reported to be de novo in one individual, although paternity was not confirmed (Proost D et al. Hum. Mutat., 2015 Aug;36:808-14; Hicks KL et al. J. Vasc. Surg., 2018 09;68:701-711; Muiño-Mosquera L et al. Circ Genom Precis Med, 2018 Jun;11:e002039). In addition, this alteration co-segregated with disease in one family tested in our laboratory (Ambry internal data, GeneDx pers. comm.). RNA studies have demonstrated that this mutation creates a new splice acceptor site that is utilized in all transcripts derived from the G allele, resulting in the inclusion of 13 intronic nucleotides and a frameshift (U. Schwarze and P. Byers, Collagen Diagnostic Laboratory, University of Washington, pers. comm.). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 13, 2023

This sequence change falls in intron 56 of the FBN1 gene. It does not directly change the encoded amino acid sequence of the FBN1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 25907466, 29510914; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 418201). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.6
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: -1
DS_AL_spliceai		0.99		Position offset: -14

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

Publications

LitVar

Other links and lift over

dbSNP: rs1064793119; hg19: chr15-48720682;