rs794728191

Variant names:

• chr15-48496101-T-C
• rs794728191
• NM_000138.5:c.2418A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-48496101-T-C
• chr15-48496101-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000138.5(FBN1):​c.2418A>G​(p.Glu806Glu) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.10

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.2418A>G	p.Glu806Glu	splice_region_variant, synonymous_variant	Exon 20 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.2418A>G	p.Glu806Glu	splice_region_variant, synonymous_variant	Exon 19 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.2418A>G	p.Glu806Glu	splice_region_variant, synonymous_variant	Exon 20 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Progeroid and marfanoid aspect-lipodystrophy syndrome Uncertain:1

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP3. -

not provided Uncertain:1

Jun 28, 2013

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Glu806Glu (GAA>GAG) in exon 20 of the FBN1 gene (NM_000138.4)The c.2418 A>G variant in the FBN1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. While the c.2418 A>G variant results in a synonymous amino acid substitution, this variant affects the nucleotide at the -2 position of the canonical splice donor site. Two different splice site prediction programs concur that this variant creates a new splice donor site and weakens the natural donor site, which can cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. With the clinical and molecular information available at this time, we cannot definitively determine if c.2418 A>G is a disease-causing mutation or a rare benign variant. The variant is found in TAAD panel(s). -

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

Jul 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 199996). This variant has been observed in individual(s) with FBN1-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 806 of the FBN1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FBN1 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs794728191; hg19: chr15-48788298;