rs140648

Positions:

• chr15-48481656-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000138.5(FBN1):​c.3963A>G​(p.Thr1321Thr) 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9381
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.21

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]

FBN1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-48481656-T-C is Pathogenic according to our data. Variant chr15-48481656-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520237.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.3963A>G	p.Thr1321Thr	splice_region_variant, synonymous_variant	32/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.3963A>G	p.Thr1321Thr	splice_region_variant, synonymous_variant	31/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.3963A>G	p.Thr1321Thr	splice_region_variant, synonymous_variant	32/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: 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	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PS1, PP4 -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2015

The c.3963A>G variant (also known as p.T1321T), located in coding exon 31, results from an A to G substitution at nucleotide position 3963 of the FBN1 gene. This nucleotide substitution does not change the amino acid at codon 1321. In one study, this substitution was found to alter the second to last nucleotide of codingexon31 and resulted inexonskipping and abnormal splicing detected byRT-PCRanalysis of total RNA isolated from cultured fibroblasts (Liu et al.Genet Test. 1997-1998;1(4):237-242).In another study, this variant was reported in a patient with predominantectopialentisand other features ofMarfansyndrome (ComeglioP et al.Br JOphthalmol. 2002: 86(12); 1359-1362).This sequence variation was also reported in a patient and his similarly affected daughter, though the authors suggested the possibility that an additional mutation may exist that was not detected byheteroduplexanalysis (HallidayD et al.Hum Genet. 1999; 105(6): 587-597). It was also detected inan individual presented with skeletal system involved, aortic dilatation and family history ofectopia lentis but did not fulfillGhentcriteria (Turner CL et al, Am. J. Med. Genet. A 2009 Feb;149A(2):161-70).This variant was previously reported in the SNPDatabase as rs140648. It<span style="font-family:arial,sans-serif; font-size:10pt">was not reported in population based cohorts in the following databases: NHLBIExomeSequencing Project (ESP)and 1000 Genomes Project. In the ESP, this variant was not observed in 6494<span style="font-family:arial,sans-serif; font-size:10pt">samples (12988 alleles) with coverage at this position.<span style="line-height:13.8667px">Using theBDGP<span style="line-height:13.8667px">andESEfinder<span style="line-height:13.8667px">splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable.<span style="font-family:arial,sans-serif; font-size:10pt">Another algorithm also predicted the variant to cause aberrant splicing (Sahashi<span style="line-height:1.6">K et al<span style="line-height:1.6">, <em style="line-height:1.6">Nucleic Acids Res<span style="line-height:1.6">. 2007<span style="line-height:1.6">; 35(18):5995-6003).Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 06, 2023

This sequence change affects codon 1321 of the FBN1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FBN1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of FBN1-related conditions (PMID: 10464652, 10647894, 12446365, 17657824, 19161152, 35058154). ClinVar contains an entry for this variant (Variation ID: 520237). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.35		Position offset: 5
DS_DL_spliceai		0.45		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs140648; hg19: chr15-48773853;