rs397515772

Variant names:

• chr15-48613007-T-TA
• rs397515772
• NM_000138.5:c.247+2dupT

Variant summary

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

The NM_000138.5(FBN1):​c.247+2dupT variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 splice_donor, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.60

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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-48613007-T-TA is Pathogenic according to our data. Variant chr15-48613007-T-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42308.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.247+2dupT		splice_donor_variant, intron_variant	Intron 3 of 65	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.247+2dupT		splice_donor_variant, intron_variant	Intron 2 of 64		NP_001393645.1
FBN1	NM_001406717.1	c.247+2dupT		splice_donor_variant, intron_variant	Intron 3 of 8		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.247+2_247+3insT		splice_donor_variant, intron_variant	Intron 3 of 65	1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.247+2_247+3insT		splice_donor_variant, intron_variant	Intron 3 of 66	1		ENSP00000453958.2
FBN1	ENST00000537463.6	n.247+2_247+3insT		splice_donor_variant, intron_variant	Intron 3 of 30	5		ENSP00000440294.2
FBN1	ENST00000674301.2	n.247+2_247+3insT		splice_donor_variant, intron_variant	Intron 3 of 67			ENSP00000501333.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Marfan syndrome Pathogenic:1

Oct 08, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.247+2dup variant in FBN1 has been previously reported in two individuals with clinical features of Marfan syndrome and segregated with disease in one affected relative (Stheneur 2009 PMID: 19293843, LMM unpublished data). In one of these individuals, the variant was reportedly a de novo occurrence Stheneur 2009 PMID: PMID: 19293843). This variant was absent from large population databases. This variant is a duplication of the thymine (T) at nucleotide position c.247+2 and is predicted to disrupt the canonical splice site (+/- 1,2), leading to an abnormal or absent protein. Loss of function of the FBN1 gene is an established disease mechanism in autosomal dominant Marfan syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PM6, PS4_Supporting. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.44		Position offset: -1
DS_DL_spliceai		0.92		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515772; hg19: chr15-48905204;