chr15-48465564-T-C

Position:

• chr15-48465564-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000138.5(FBN1):​c.4942+4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 splice_region, intron
• Scores: Splicing: ADA: 0.9560
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.682

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.4942+4A>G		splice_region_variant, intron_variant		ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.4942+4A>G		splice_region_variant, intron_variant			NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.4942+4A>G		splice_region_variant, intron_variant		1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	Jul 19, 2019	The c.4942+4A>G variant was found in one individual with Marfan Syndrome. This variant has an entry in the ClinVar (Variation ID:42374). Evaluation at our clinical center was done with in silico method with the use of NetGene2, Human Splicing Finder. Although calculations show probable affection on splicing, we classify it as uncertain significance. Functional study deemed necessary. -
Uncertain significance, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PP6, PP4 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 28, 2006

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 16, 2019

Not observed in large population cohorts (Lek et al., 2016); In-silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing; in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; Reported in ClinVar (ClinVar Variant ID 42374; Landrum et al., 2016); Reported in a child who fulfilled diagnostic criteria for Marfan syndrome, though clinical details were not provided (Lerner-Ellis et al., 2014); This variant is associated with the following publications: (PMID: 24793577) -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 22, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 42374). This variant has been observed in individual(s) with clinical features of FBN1-related disease (PMID: 24793577; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 40 of the FBN1 gene. It does not directly change the encoded amino acid sequence of the FBN1 protein. It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	18
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.96
dbscSNV1_RF	Benign	0.67
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: 14
DS_DL_spliceai		0.32		Position offset: 4

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515815; hg19: chr15-48757761;