rs1060501065

chr15-48412707-GT-G

Variant summary

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

The NM_000138.5(FBN1):c.8087del(p.Asn2696ThrfsTer56) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.707

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 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 64 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-48412707-GT-G is Pathogenic according to our data. Variant chr15-48412707-GT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 406336.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.8087del	p.Asn2696ThrfsTer56	frameshift_variant	65/66	ENST00000316623.10
FBN1	NM_001406716.1	c.8087del	p.Asn2696ThrfsTer56	frameshift_variant	64/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.8087del	p.Asn2696ThrfsTer56	frameshift_variant	65/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Marfan syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 23, 2016

This sequence change deletes 1 nucleotide from exon 65 of the FBN1 mRNA (c.8087delA), causing a frameshift at codon 2696. This creates a premature translational stop signal in the last exon of the FBN1 mRNA (p.Asn2696Thrfs*56). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 119 amino acids of the FBN1 protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FBN1-related disease. A different truncating variant downstream from this event (c.8534dup, p.Glu2846Argfs*5) has been determined to be pathogenic (PMID: 19293843). This suggests that the residues downstream are critical for FBN1 protein function and that other truncating variants that do not result in nonsense mediated decay may also be pathogenic. In summary, this variant is a novel deletion that affects residues critical for FBN1 function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 23, 2016

In summary, this variant is a novel deletion that affects residues critical for FBN1 function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. A different truncating variant downstream from this event (c.8534dup, p.Glu2846Argfs*5) has been determined to be pathogenic (PMID: 19293843). This suggests that the residues downstream are critical for FBN1 protein function and that other truncating variants that do not result in nonsense mediated decay may also be pathogenic. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FBN1-related disease. This sequence change deletes 1 nucleotide from exon 65 of the FBN1 mRNA (c.8087delA), causing a frameshift at codon 2696. This creates a premature translational stop signal in the last exon of the FBN1 mRNA (p.Asn2696Thrfs*56). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 119 amino acids of the FBN1 protein. -

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: rs1060501065; hg19: chr15-48704904;