rs1555393539

Positions:

• chr15-48411200-G-GC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000138.5(FBN1):​c.8405_8406insG​(p.Phe2803LeufsTer3) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.11

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 26 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-48411200-G-GC is Pathogenic according to our data. Variant chr15-48411200-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 520233.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.8405_8406insG	p.Phe2803LeufsTer3	frameshift_variant	66/66	ENST00000316623.10
FBN1	NM_001406716.1	c.8405_8406insG	p.Phe2803LeufsTer3	frameshift_variant	65/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.8405_8406insG	p.Phe2803LeufsTer3	frameshift_variant	66/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2016

The c.8405dupG pathogenic mutation, located in coding exon 65 of the FBN1 gene, results from a duplication of one nucleotide at position 8405, causing a translational frameshift with a predicted alternate stop codon (p.F2803Lfs*3). Frameshifts are typically deleterious in nature; however, this frameshift occurs at the 3' terminus of FBN1, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 69 amino acids of the C-terminal propeptide of the protein. Although the exact functional impact of these altered amino acids is unknown at this time, a functional study has demonstrated that other truncations within the C-terminal propeptide (both 5' and 3' of this alteration) interfere with FBN1 secretion (Jensen SA et al. Proc. Natl. Acad. Sci. U.S.A. 2014;111:10155-60). In addition, a number of truncations past this position have been reported in individuals with Marfan syndrome in the literature. This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555393539; hg19: chr15-48703397;