rs1555399205

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The ENST00000316623.10(FBN1):​c.2463C>G​(p.Cys821Trp) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C821S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

FBN1
ENST00000316623.10 missense

Scores

11
4
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.72
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in ENST00000316623.10
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr15-48495546-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3337101.Status of the report is criteria_provided_single_submitter, 1 stars.
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
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
Variant 15-48495545-G-C is Pathogenic according to our data. Variant chr15-48495545-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 519723.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FBN1NM_000138.5 linkuse as main transcriptc.2463C>G p.Cys821Trp missense_variant 21/66 ENST00000316623.10 NP_000129.3
FBN1NM_001406716.1 linkuse as main transcriptc.2463C>G p.Cys821Trp missense_variant 20/65 NP_001393645.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FBN1ENST00000316623.10 linkuse as main transcriptc.2463C>G p.Cys821Trp missense_variant 21/661 NM_000138.5 ENSP00000325527 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMay 03, 2021The p.C821W variant (also known as c.2463C>G), located in coding exon 20 of the FBN1 gene, results from a C to G substitution at nucleotide position 2463. The cysteine at codon 821 is replaced by tryptophan, an amino acid with highly dissimilar properties, and is located in the cb EGF-like #09 domain. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Other alterations affecting this amino acid (p.C821Y, c.2462G>A and p.C821F, c.2462G>T) have been detected in cases reported to have Marfan syndrome (Hung CC et al. Ann Hum Genet. 2009;73(Pt 6):559-67; Franken R et al. Eur Heart J. 2016 Jan. Epub ahead of print). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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). Based on internal structural assessment, this alteration eliminates a structurally critical disulfide bond in the structurally sensitive EGF/cbEGF domain #09. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
26
DANN
Uncertain
0.99
Eigen
Pathogenic
0.72
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.85
T
M_CAP
Pathogenic
0.72
D
MetaRNN
Pathogenic
1.0
D
MetaSVM
Pathogenic
0.84
D
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-8.7
D
REVEL
Pathogenic
0.81
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Vest4
0.98
MutPred
0.98
Loss of methylation at K822 (P = 0.0268);
MVP
0.98
MPC
2.5
ClinPred
1.0
D
GERP RS
2.0

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

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

Other links and lift over

dbSNP: rs1555399205; hg19: chr15-48787742; API