rs144189837

Positions:

chr15-48425443-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP2PP3BS2

The NM_000138.5(FBN1):c.7379A>G(p.Lys2460Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000106 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

FBN1
NM_000138.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:15

Conservation

PhyloP100: 6.26

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000138.5

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN1. . Gene score misZ 5.0644 (greater than the threshold 3.09). Trascript score misZ 8.1787 (greater than threshold 3.09). GenCC has associacion of gene with MASS syndrome, Weill-Marchesani syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, Acromicric dysplasia, familial thoracic aortic aneurysm and aortic dissection, progeroid and marfanoid aspect-lipodystrophy syndrome, ectopia lentis 1, isolated, autosomal dominant, Marfan syndrome, Weill-Marchesani syndrome 2, dominant, isolated ectopia lentis, neonatal Marfan syndrome, stiff skin syndrome.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5 linkuse as main transcript	c.7379A>G	p.Lys2460Arg	missense_variant	60/66	ENST00000316623.10
FBN1	NM_001406716.1 linkuse as main transcript	c.7379A>G	p.Lys2460Arg	missense_variant	59/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10 linkuse as main transcript	c.7379A>G	p.Lys2460Arg	missense_variant	60/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

251300

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000109

AC:

160

AN:

1461844

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000136

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000887

Hom.:

Bravo

AF:

0.0000642

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2024	Has been reported in association with Marfan syndrome in published literature, and frequently referred to as a variant of uncertain significance (PMID: 17627385, 21895641, 24941995, 25644172, 29907982); Reported in cis with FBN1 p.(N542S) in a patient with bicuspid aortic valve, TAAD, and additional connective tissue features who also harbored variants in TGFBR3, NOTCH1, and LTBP1; the FBN1 variants segregated with systemic connective tissue features in his mother, and the TGFBR3 variant segregated with aortic root dilation in his father and siblings (PMID: 30255099); At the protein level, in silico analysis indicates that this missense variant does not alter protein structure/function; At the mRNA level, in silico analysis supports a deleterious effect on splicing; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); This variant is associated with the following publications: (PMID: 24055113, 25812041, 25637381, 24941995, 32123317, 25644172, 21895641, 29907982, 17627385, 34663891, 30255099, 12938084) -
Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 16, 2021	No ACMG evidence could be applied applied -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 26, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Marfan syndrome

Uncertain:3

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This missense variant replaces lysine with arginine at codon 2460 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may impact RNA splicing. However, an RNA study showed no abnormal splicing (PMID: 32123317). This variant has been reported in one individual affected with Marfan syndrome or Marfan-like phenotype (PMID: 17627385, 21895641) and in an individual affected with bicuspid aortic valve, a common congenital heart defect with increased prevalence of aortic dilatation/dissection (PMID: 30255099). This variant was also reported in an individual with aortic dissection and suspected hereditary thoracic aortic disease (PMID: 29907982) along with another individual who was affected with non-syndromic heritable thoracic aortic disorder (PMID: 25644172). This variant has also been identified in 20/282708 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 20, 2023	This missense variant replaces lysine with arginine at codon 2460 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may impact RNA splicing. However, an RNA study showed no abnormal splicing (PMID: 32123317). This variant has been reported in one individual affected with Marfan syndrome or Marfan-like phenotype (PMID: 17627385, 21895641) and in an individual affected with bicuspid aortic valve, a common congenital heart defect with increased prevalence of aortic dilatation/dissection (PMID: 30255099). This variant was also reported in an individual with aortic dissection and suspected hereditary thoracic aortic disease (PMID: 29907982) along with another individual who was affected with non-syndromic heritable thoracic aortic disorder (PMID: 25644172). This variant has also been identified in 20/282708 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 26, 2022	The p.K2460R variant (also known as c.7379A>G), located in coding exon 59 of the FBN1 gene, results from an A to G substitution at nucleotide position 7379. The lysine at codon 2460 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in individuals from cohorts with Marfan syndrome or Marfan-like features; however, details were limited (Campens L et al. Orphanet J Rare Dis, 2015 Feb;10:9; Howarth R et al. Genet. Test., 2007;11:146-52). This variant was also detected in probands with bicuspid aortic valve, aortic dissection/dilation, and systemic features; however, other variants were also detected (Overwater E et al. Hum Mutat. 2018 09;39(9):1173-1192; Sticchi E et al. Biomed Res Int. 2018 Sep;2018:8386123). This alteration has also been seen in exome cohorts, but cardiovascular history was not provided (Dorschner MO et al. Am. J. Hum. Genet., 2013 Oct;93:631-40; Amendola LM et al. Genome Res., 2015 Mar;25:305-15). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 26, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 Marfan proband, 4/5 papers in HGMD classify as VUS due to presence in ESP. ClinVar: 2 VUS -

FBN1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 16, 2024

The FBN1 c.7379A>G variant is predicted to result in the amino acid substitution p.Lys2460Arg. This variant was reported in multiple individuals with Marfan syndrome or related aortopathies (Howarth et al. 2007. PubMed ID: 17627385; Robinson et al. 2012. PubMed ID: 21895641; Campens et al. 2015. PubMed ID: 25644172; Growth et al. 2016. PubMed ID: 25812041). However, this variant was also found to co-occur with other rare variants in genes associated with Marfan syndrome phenotypes (Table S1, Overwater et al. 2018. PubMed ID: 29907982; Sticchi et al. 2018. PubMed ID: 30255099). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is more common than expected for disease-causing variant. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Jan 31, 2024

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 2460 of the FBN1 protein (p.Lys2460Arg). This variant is present in population databases (rs144189837, gnomAD 0.01%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of Marfan syndrome and thoracic aortic disorders (PMID: 17627385, 21895641, 25644172, 29907982, 30255099). ClinVar contains an entry for this variant (Variation ID: 161239). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.80

MetaSVM

Uncertain

0.13

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.6

REVEL

Pathogenic

0.71

Sift

Benign

0.26

Sift4G

Benign

0.24

Vest4

0.64

MVP

0.93

MPC

1.0

ClinPred

0.24

GERP RS

5.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.52

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.52

Position offset: -1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over