chr15-48411189-A-AT

Position:

• chr15-48411189-A-AT

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_00138 c.8416dup, is predicted to cause a frameshift resulting in a premature stop codon at position 2833, leading to a truncated protein. This variant is located in the coding exon 65 of the gene and is not expected to undergo nonsense-mediated decay. Premature terminations in the C-terminus are considered to be deleterious (PVS1_Strong; PMID 24982166, 12161601, 7911051, 21034599). This variant was found in a proband with thoracic aortic dissection and a systemic score >7, which is a highly specific phenotype for Marfan syndrome (MFS) (Internal lab data, PMID 29875124, PP4). This variant has been reported twice in ClinVar, once as pathogenic and once as uncertain significance (Variation ID: 547349). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1_Strong, PM2_Sup, PP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA658824375/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 4.98

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]

FBN1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.8416dupA	p.Ile2806fs	frameshift_variant	66/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.8416dupA	p.Ile2806fs	frameshift_variant	65/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.8416dupA	p.Ile2806fs	frameshift_variant	66/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	Aug 22, 2024	The NM_00138 c.8416dup, is predicted to cause a frameshift resulting in a premature stop codon at position 2833, leading to a truncated protein. This variant is located in the coding exon 65 of the gene and is not expected to undergo nonsense-mediated decay. Premature terminations in the C-terminus are considered to be deleterious (PVS1_Strong; PMID 24982166, 12161601, 7911051, 21034599). This variant was found in a proband with thoracic aortic dissection and a systemic score >7, which is a highly specific phenotype for Marfan syndrome (MFS) (Internal lab data, PMID 29875124, PP4). This variant has been reported twice in ClinVar, once as pathogenic and once as uncertain significance (Variation ID: 547349). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1_Strong, PM2_Sup, PP4 -

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: rs1555393538; hg19: chr15-48703386;