rs727505269

chr15-48537686-AG-A

Variant summary

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

The NM_000138.5(FBN1):c.660del(p.Cys221ValfsTer109) 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P220P) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.896

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-48537686-AG-A is Pathogenic according to our data. Variant chr15-48537686-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 179992.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.660del	p.Cys221ValfsTer109	frameshift_variant	7/66	ENST00000316623.10
FBN1	NM_001406716.1	c.660del	p.Cys221ValfsTer109	frameshift_variant	6/65
FBN1	NM_001406717.1	c.660del	p.Cys221ValfsTer78	frameshift_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.660del	p.Cys221ValfsTer109	frameshift_variant	7/66	1	NM_000138.5	P1
FBN1	ENST00000559133.6	c.660del	p.Cys221ValfsTer109	frameshift_variant, NMD_transcript_variant	7/67	1
FBN1	ENST00000674301.2	c.660del	p.Cys221ValfsTer109	frameshift_variant, NMD_transcript_variant	7/68
FBN1	ENST00000537463.6	c.636+24del		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Marfan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 30, 2014

The p.Cys221fs variant in FBN1 has not been reported in individuals with clinica l features of Marfan syndrome or in large population studies. This variant is pr edicted to cause a frameshift, which alters the protein?s amino acid sequence be ginning at position 221 and leads to a premature termination codon 109 amino aci ds downstream. This alteration is then predicted to lead to a truncated or absen t protein. Heterozygous loss of function of function of the FBN1 gene is an esta blished disease mechanism in Marfan syndrome. In summary, this variant meets our criteria to be classified as pathogenic for Marfan syndrome in an autosomal dom inant manner (http://www.partners.org/personalizedmedicine/LMM). -

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: rs727505269; hg19: chr15-48829883;