15-48468107-T-C

Position:

• chr15-48468107-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3 PP4 PM2_Supporting PS4_Moderate PM6_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000138.5 c.4583-5A>G variant in FBN1 is a variant in the splice acceptor region of intron 37. Computational splice prediction algorithms predict that this variant impacts splicing (PP3). This variant was identified in the literature and public databases in two individuals with clinical diagnoses of Marfan syndrome including once as de novo in an individual with phenotype consistent with but not highly specific to FBN1 and in an individual with aortic aneurysm and other features suggestive of Marfan syndrome; it was also found to segregate with disease in at least one affected family member (PS4_moderate, PM6_supporting; PMID:25101912, Invitae internal data, ClinVar ID: 406332). It was also identified in a third individual with a clinical diagnosis of Marfan syndrome (PP4; Johns Hopkins). This variant is not present in gnomAD v2.1.1 or v3.1.2 (PM2_supporting; https://gnomad.broadinstitute.org/). 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 (PS4_moderate, PM2_supporting, PM6_supporting, PP3, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16614422/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 1.46

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 Likely_pathogenic. Variant got 6 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.4583-5A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000316623.10
FBN1	NM_001406716.1	c.4583-5A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.4583-5A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

Jun 15, 2023

The NM_000138.5 c.4583-5A>G variant in FBN1 is a variant in the splice acceptor region of intron 37. Computational splice prediction algorithms predict that this variant impacts splicing (PP3). This variant was identified in the literature and public databases in two individuals with clinical diagnoses of Marfan syndrome including once as de novo in an individual with phenotype consistent with but not highly specific to FBN1 and in an individual with aortic aneurysm and other features suggestive of Marfan syndrome; it was also found to segregate with disease in at least one affected family member (PS4_moderate, PM6_supporting; PMID: 25101912, Invitae internal data, ClinVar ID: 406332). It was also identified in a third individual with a clinical diagnosis of Marfan syndrome (PP4; Johns Hopkins). This variant is not present in gnomAD v2.1.1 or v3.1.2 (PM2_supporting; https://gnomad.broadinstitute.org/). 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 (PS4_moderate, PM2_supporting, PM6_supporting, PP3, PP4). -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2018

This sequence change falls in intron 37 of the FBN1 mRNA. It does not directly change the encoded amino acid sequence of the FBN1 protein. This variant is not present in population databases (ExAC no frequency). In summary this is a rare intronic variant that is predicted to affect protein splicing and has been reported as de novo in an affected individual. For these reasons, this variant has ben classified as Likely Pathogenic. Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this intronic variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. This sequence change was reported as de novo in an individual affected with Marfan syndrome (PMID: 25101912, 25652356). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs778966916; hg19: chr15-48760304;