rs1057518501

chr15-48468528-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP3

The NM_000138.5(FBN1):c.4466A>G(p.Asn1489Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1489K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 8.02

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_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-48468527-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, FBN1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.4466A>G	p.Asn1489Ser	missense_variant	37/66	ENST00000316623.10
FBN1	NM_001406716.1	c.4466A>G	p.Asn1489Ser	missense_variant	36/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.4466A>G	p.Asn1489Ser	missense_variant	37/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

Jun 15, 2023

The NM_000138 c.4466A>G variant is a missense variant in FBN1 predicted to cause a substitution of asparagine by serine at amino position 1489. This variant has not been reported in the literature but has been reported in ClinVar three times as a variant of uncertain significance (Variation ID: 373598). This variant lies in a critical calcium binding site within a calcium-binding EGF domain; however, since asparagine to serine substitutions in these positions might be tolerated (PMID: 31227806) the PM1 criterion has not been used. It is not present in gnomAD v2.1.1 nor v3.1.2 (PM2_supporting; https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis are unclear about the predicted impact of this variant (REVEL = 0.556). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). Another missense variant at the same position (p.Asn1489Lys) is classified as likely pathogenic (PM5; PMIDs: 20082464, 26621581; 21542060). Due to the insufficient evidence, this variant is classified as of uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM2_supporting, PP2, PM5. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 29, 2016

A variant of uncertain significance has been identified in the FBN1 gene. The N1489S variant has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. This variant was not observed in the Exome Aggregation Consortium or in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although the N1489S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, it occurs at a position that is conserved in mammals. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, although the N1489S variant is located within a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a Cysteine residue. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003). It should be noted that another missense substitution at the same residue (N1489K) has been reported in the Human Gene Mutation Database in association with Marfan syndrome (Stenson et al., 2014); however, it also does not affect a Cysteine residue. Additionally, although several missense substitutions in nearby residues (C1485G, C1485R, C1485Y, D1487A, C1491F, C1491Y) have been reported in association with Marfan syndrome (Stenson et al., 2014), the majority of them do affect a Cysteine residue.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. This result cannot be interpreted for diagnosis or used for family member screening at this time. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 14, 2021

This sequence change replaces asparagine with serine at codon 1489 of the FBN1 protein (p.Asn1489Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 373598). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant disrupts the p.Asn1489 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 20082464, 21542060, 26621581), which suggests that this may be a clinically significant amino acid residue. 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. -

Marfan syndrome;C0265287:Acromicric dysplasia;C1858556:MASS syndrome;C1861456:Stiff skin syndrome;C1869115:Weill-Marchesani syndrome 2, dominant;C3280054:Geleophysic dysplasia 2;C3541518:Ectopia lentis 1, isolated, autosomal dominant;C4310796:Progeroid and marfanoid aspect-lipodystrophy syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 27, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.50	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.014	D
Vest4		0.72
MutPred		0.66		Gain of disorder (P = 0.087);
MVP		0.93
MPC		0.60
ClinPred		0.95	D
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1057518501; hg19: chr15-48760725;