rs397515772

Positions:

• chr15-48613007-T-TA

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_000138.5(FBN1):​c.247+2_247+3insT variant causes a splice region, 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_region, 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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• 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/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.247+2_247+3insT		splice_region_variant, intron_variant		ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.247+2_247+3insT		splice_region_variant, intron_variant			NP_001393645.1
FBN1	NM_001406717.1	c.247+2_247+3insT		splice_region_variant, intron_variant			NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.247+2_247+3insT		splice_region_variant, intron_variant		1	NM_000138.5	ENSP00000325527	P1
FBN1	ENST00000559133.6	c.247+2_247+3insT		splice_region_variant, intron_variant, NMD_transcript_variant		1		ENSP00000453958
FBN1	ENST00000537463.6	c.247+2_247+3insT		splice_region_variant, intron_variant, NMD_transcript_variant		5		ENSP00000440294
FBN1	ENST00000674301.2	c.247+2_247+3insT		splice_region_variant, intron_variant, NMD_transcript_variant				ENSP00000501333

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 08, 2020

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;