rs1555397655

chr15-48474293-CACAG-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000138.5(FBN1):c.4168_4171del(p.Leu1390AlafsTer22) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L1390L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.05

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 15-48474293-CACAG-C is Pathogenic according to our data. Variant chr15-48474293-CACAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 517371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.4168_4171del	p.Leu1390AlafsTer22	frameshift_variant	34/66	ENST00000316623.10
FBN1	NM_001406716.1	c.4168_4171del	p.Leu1390AlafsTer22	frameshift_variant	33/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.4168_4171del	p.Leu1390AlafsTer22	frameshift_variant	34/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PVS1, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 27, 2017	The p.Leu1390fs variant in FBN1 has been reported in one Chinese individual with clinical features of Marfan syndrome, segregated with disease in one affected r elative (Wang 2013) and was absent from large population studies, though the abi lity of these studies to accurately detect indels may be limited. This variant i s predicted to cause a frameshift, which alters the protein?s amino acid sequenc e beginning at position 1930 and leads to a premature termination codon 22 amino acids downstream. This alteration is then predicted to lead to a truncated or a bsent protein. Heterozygous loss of function of the FBN1 gene is an established disease mechanism in Marfan syndrome. In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome in an autosomal dominant manner based upon the predicted impact to the protein and absence in controls. -

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: rs1555397655; hg19: chr15-48766490;