NM_000138.5:c.6872-14A>G

Variant names:

• chr15-48428485-T-C
• rs1064793119
• NM_000138.5:c.6872-14A>G

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 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 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 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 rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.6872-14A>G		intron_variant	Intron 56 of 65	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.6872-14A>G		intron_variant	Intron 55 of 64		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.6872-14A>G		intron_variant	Intron 56 of 65	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Marfan syndrome Pathogenic:2 Uncertain:2

Mar 01, 2021

Centre of Medical Genetics, University of Antwerp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

PM2, PP3, PP1, PP4 -

Jan 02, 2025

Department of Laboratory Medicine and Genetics, Samsung Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NM_000138.5:c.6872-14A>G is considered to be rare in the general population database (gnomAD v2.1.1). This variant is predicted to be deleterious by in-silico analysis (SpliceAI). This variant was found in a patient with Marfan syndrome meeting revised Ghent criteria and considered as de novo variant (PMID: 25907466; 29875124; 35058154). According to the ClinGen guidance for PP1/BS4 and PP4 criteria (PMID: 38103548), PP4 with weighted strength was applied. In summary, this variant was classified as a likely pathogenic variant for Marfan syndrome (PP3, PP4 with weighted strength, PS4_P, PM2_P, PM6_P). -

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 07, 2017

Center for Medical Genetics Ghent, University of Ghent

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

not provided Pathogenic:1 Uncertain:1

May 29, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Dec 27, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Sep 26, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 23, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FBN1 c.6872-14A>G alters a nucleotide located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 3' acceptor site. Four predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251228 control chromosomes. c.6872-14A>G has been reported in the literature in individuals affected with Marfan Syndrome (Muino-Mosquera_2018, Proost_2015, Meester_2022) including a de novo occurrence. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29510914, 35058154, 25907466, 29875124). ClinVar contains an entry for this variant (Variation ID: 418201). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; internal data). 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;