rs1555405056

Positions:

• chr15-48600236-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000138.5(FBN1):​c.347-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 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_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.21

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, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.011025998 fraction of the gene. Cryptic splice site detected, with MaxEntScore 13, offset of -1, new splice context is: ttcttcttcttttttttcAGgta. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-48600236-T-C is Pathogenic according to our data. Variant chr15-48600236-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 519716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.347-2A>G		splice_acceptor_variant, intron_variant		ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.347-2A>G		splice_acceptor_variant, intron_variant			NP_001393645.1
FBN1	NM_001406717.1	c.347-2A>G		splice_acceptor_variant, intron_variant			NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.347-2A>G		splice_acceptor_variant, intron_variant		1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.347-2A>G		splice_acceptor_variant, intron_variant		1		ENSP00000453958.2
FBN1	ENST00000537463.6	n.347-2A>G		splice_acceptor_variant, intron_variant		5		ENSP00000440294.2
FBN1	ENST00000674301.2	n.347-2A>G		splice_acceptor_variant, intron_variant				ENSP00000501333.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 17, 2019	The c.347-2A>G variant in FBN1 has been previously reported in 1 individual with Marfan syndrome, segregated with disease in 1 affected family member (Magyar 2009), and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 519716). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Furthermore, in vivo functional studies suggest the creation of an alternate splice site leading to a frameshift (Magyar 2009). In summary, although additional studies are required to fully establish its clinical significance, the c.347-2A>G variant meets criteria to be classified as likely pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PM2, PS3_Supporting, PS4_Supporting. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 23, 2017

The c.347-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 4 in the FBN1 gene. This alteration was previously described in a family with Marfan syndrome (Magyar I et al. Hum Mutat. 2009;30(9):1355-64), and in the same study, mRNA analysis demonstrated aberrant splicing causing a frameshift with a predicted alternate stop codon. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as disease-causing mutation. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 11, 2023

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in altered splicing and introduces a premature termination codon (PMID: 19618372). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 519716). Disruption of this splice site has been observed in individuals with Marfan syndrome (PMID: 19618372; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 4 of the FBN1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
GERP RS		6.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: -1
DS_AL_spliceai		0.87		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555405056; hg19: chr15-48892433;