rs201309310

Positions:

chr15-48644711-T-C

Variant summary

Our verdict is Uncertain significance. Variant got -5 ACMG points: 0P and 5B. BP2BS1

This summary comes from the ClinGen Evidence Repository: The NM_000138 c.59A>G, is a missense variant in FBN1 predicted to cause a substitution of a Tyrosine by a Cysteine at amino acid 20 (p.Tyr20Cys). This variant was found in a proband with aortic root dilatation and a systemic score of 7 or above which is a highly specific phenotype for Marfan syndrome, however, a pathogenic splice variant in FBN1 was also identified in cis in this individual (BP2). The variant segregates with the disease in 4 affected family members, who also carry the pathogenic splice variant in FBN1. The variant in FBN1 has been reported 12 times in ClinVar: 3 times as likely benign, 8 times as uncertain significance and once as likely pathogenic (Variation ID: 161245). This variant has been identified in 37 individuals of European non-Finnish origin (MAF: 0.029%) (BS1; https://gnomad.broadinstitute.org/ version 2.1.1). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of two benign arguments, PP2 cannot be used. In summary, this variant meets criteria to be classified as likely benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS1, BP2 LINK:https://erepo.genome.network/evrepo/ui/classification/CA016208/MONDO:0007947/022

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

FBN1
NM_000138.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:10B:3

Conservation

PhyloP100: 3.86

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 -5 ACMG points.

BP2

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
FBN1	NM_000138.5 linkuse as main transcript	c.59A>G	p.Tyr20Cys	missense_variant	2/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1 linkuse as main transcript	c.59A>G	p.Tyr20Cys	missense_variant	1/65		NP_001393645.1
FBN1	NM_001406717.1 linkuse as main transcript	c.59A>G	p.Tyr20Cys	missense_variant	2/9		NP_001393646.1
FBN1	NM_001406718.1 linkuse as main transcript	c.59A>G	p.Tyr20Cys	missense_variant	2/3		NP_001393647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10 linkuse as main transcript	c.59A>G	p.Tyr20Cys	missense_variant	2/66	1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000147

AC:

AN:

251386

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135874

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:

0.0000653

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000256

AC:

374

AN:

1461816

Hom.:

Cov.:

AF XY:

0.000231

AC XY:

168

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000316

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000164

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000152

Hom.:

Bravo

AF:

0.000132

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:10Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:5Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 09, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2023	Does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25812041, 25637381, 26017485, 16222657, 24941995, 29543232, 12938084) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 20, 2017	Variant summary: The FBN1 c.59A>G (p.Tyr20Cys) variant involves the alteration of a conserved nucleotide and 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have yet to be functionally assessed. This variant was found in 41/277062 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0003 (38/126638). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic FBN1 variant (0.0001125), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. This variant has been reported in multiple affected individuals without strong evidence for causality. Although, one paper, Yang_2014 indicates the variant does segregate with disease in the family, however, clinical information is not provided for additional family members. In addition, multiple clinical diagnostic laboratories/reputable databases and publications classified this variant with conflicting classifications "uncertain significance" or "likely benign." Taken together, this variant is classified as likely benign. -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 07, 2021	The p.Y20C variant (also known as c.59A>G), located in coding exon 1 of the FBN1 gene, results from an A to G substitution at nucleotide position 59. The tyrosine at codon 20 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the signal peptide domain. This alteration has been reported in an individual with skeletal involvement and pneumothorax as well as individuals with abdominal and thoracic aortic aneurysms (Arbustini E et al. Hum Mutat, 2005 Nov;26:494; van de Luijtgaarden KM et al. Hum Genet, 2015 Aug;134:881-93; Weerakkody R et al. Genet Med, 2018 11;20:1414-1422). This variant has also been seen in an exome cohort, but cardiovascular history was not provided (Amendola LM et al. Genome Res, 2015 Mar;25:305-15). The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely pathogenic, no assertion criteria provided	research	Centre for Genomic and Experimental Medicine, University of Edinburgh	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 06, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 22, 2022	- -

Marfan syndrome

Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	Dec 01, 2022	The NM_000138 c.59A>G, is a missense variant in FBN1 predicted to cause a substitution of a Tyrosine by a Cysteine at amino acid 20 (p.Tyr20Cys). This variant was found in a proband with aortic root dilatation and a systemic score of 7 or above which is a highly specific phenotype for Marfan syndrome, however, a pathogenic splice variant in FBN1 was also identified in cis in this individual (BP2). The variant segregates with the disease in 4 affected family members, who also carry the pathogenic splice variant in FBN1. The variant in FBN1 has been reported 12 times in ClinVar: 3 times as likely benign, 8 times as uncertain significance and once as likely pathogenic (Variation ID: 161245). This variant has been identified in 37 individuals of European non-Finnish origin (MAF: 0.029%) (BS1; https://gnomad.broadinstitute.org/ version 2.1.1). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of two benign arguments, PP2 cannot be used. In summary, this variant meets criteria to be classified as likely benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS1, BP2 -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 31, 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: Multiple papers report as VUS; ExAC: 16/66648 Europeans; ClinVar: 1 LB, 2 VUS -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.049

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.38

.;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.084

MetaRNN

Benign

0.38

T;T

MetaSVM

Benign

-0.83

MutationTaster

Benign

0.90

N;N

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.67

N;D

REVEL

Uncertain

0.37

Sift

Benign

0.17

T;D

Sift4G

Benign

0.19

T;T

Vest4

0.78

MVP

0.97

MPC

0.88

ClinPred

0.094

GERP RS

3.5

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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