rs1555405039

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate

The NM_000138.5(FBN1):​c.408C>G​(p.Cys136Trp) 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 (★).

Frequency

Genomes: not found (cov: 33)

Consequence

FBN1
NM_000138.5 missense

Scores

11
5
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.54
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 11 ACMG points.

PM1
In a region_of_interest Interaction with MFAP4 (size 210) in uniprot entity FBN1_HUMAN there are 27 pathogenic changes around while only 6 benign (82%) in NM_000138.5
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the FBN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 1311 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.0644 (above the threshold of 3.09). Trascript score misZ: 8.1787 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.994
PP5
Variant 15-48600173-G-C is Pathogenic according to our data. Variant chr15-48600173-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520235.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBN1NM_000138.5 linkc.408C>G p.Cys136Trp missense_variant Exon 5 of 66 ENST00000316623.10 NP_000129.3 P35555
FBN1NM_001406716.1 linkc.408C>G p.Cys136Trp missense_variant Exon 4 of 65 NP_001393645.1
FBN1NM_001406717.1 linkc.408C>G p.Cys136Trp missense_variant Exon 5 of 9 NP_001393646.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBN1ENST00000316623.10 linkc.408C>G p.Cys136Trp missense_variant Exon 5 of 66 1 NM_000138.5 ENSP00000325527.5 P35555
FBN1ENST00000559133.6 linkn.408C>G non_coding_transcript_exon_variant Exon 5 of 67 1 ENSP00000453958.2 H0YND0
FBN1ENST00000537463.6 linkn.408C>G non_coding_transcript_exon_variant Exon 5 of 31 5 ENSP00000440294.2 F6U495
FBN1ENST00000674301.2 linkn.408C>G non_coding_transcript_exon_variant Exon 5 of 68 ENSP00000501333.2 A0A6I8PL22

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
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
Feb 14, 2023
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.C136W variant (also known as c.408C>G), located in coding exon 4 of the FBN1 gene, results from a C to G substitution at nucleotide position 408. The cysteine at codon 136 is replaced by tryptophan, an amino acid with highly dissimilar properties. Alterations affecting the same amino acid, p.C136S (c.406T>A), p.C136R (c.406T>C) and p.C136F(c.407G>T) have been reported in association with Marfan syndrome (Attanasio M et al, Clin. Genet. 2008 Jul; 74(1):39-46; Groth KA et al. Genet. Med., 2017 07;19:772-777). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). Based on internal structural assessment, this alteration eliminates a structurally critical disulfide in the structurally sensitive EGF-like domain #02. 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, this alteration is predicted to be deleterious by in silico analysis. 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
0.52
D
BayesDel_noAF
Pathogenic
0.52
CADD
Uncertain
24
DANN
Uncertain
0.99
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.95
D
M_CAP
Pathogenic
0.71
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.0
D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-8.5
D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Vest4
0.93
MutPred
0.97
Loss of disorder (P = 0.0087);
MVP
0.99
MPC
1.7
ClinPred
1.0
D
GERP RS
4.3

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs1555405039; hg19: chr15-48892370; API