rs201309310

chr15-48644711-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1 PP2 BP4 BP6_Strong BS2

The NM_000138.5(FBN1):c.59A>G(p.Tyr20Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000247 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:10 B:3
• Conservation: PhyloP100: 3.86

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 Likely_benign. Variant got -6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 10 uncertain in NM_000138.5
• PP2: Missense variant where missense usually causes diseases, FBN1
• BP4: Computational evidence support a benign effect (MetaRNN=0.3831257).
• BP6: Variant 15-48644711-T-C is Benign according to our data. Variant chr15-48644711-T-C is described in ClinVar as [Uncertain_significance]. Clinvar id is 161245.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=3}.
• BS2: High AC in GnomAd at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.59A>G	p.Tyr20Cys	missense_variant	2/66	ENST00000316623.10
FBN1	NM_001406716.1	c.59A>G	p.Tyr20Cys	missense_variant	1/65
FBN1	NM_001406717.1	c.59A>G	p.Tyr20Cys	missense_variant	2/9
FBN1	NM_001406718.1	c.59A>G	p.Tyr20Cys	missense_variant	2/3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152152 Hom.: 0 Cov.: 33

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: 37 AN: 251386 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135874

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.: 0 Cov.: 30 AF XY: 0.000231 AC XY: 168 AN XY: 727210

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: 25 AN: 152270 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74448

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.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

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

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:5 Benign:1

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	Feb 08, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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 (Collod-Beroud et al., 2003).; 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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 09, 2015	- -
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:1 Uncertain:2 Benign: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. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 22, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 06, 2020	- -
Likely pathogenic, no assertion criteria provided	research	Centre for Genomic and Experimental Medicine, University of Edinburgh	-	- -

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

Invitae

Jan 06, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Uncertain	0.0
Cadd	Benign	22
Dann	Benign	0.96
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	0.90	N;N
PrimateAI	Uncertain	0.74	T
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	T
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

Other links and lift over

dbSNP: rs201309310; hg19: chr15-48936908;