rs1555398673

Variant names:

• chr15-48488433-A-G
• rs1555398673
• NM_000138.5:c.3143T>C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):​c.3143T>C​(p.Ile1048Thr) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.32

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a disulfide_bond (size 14) in uniprot entity FBN1_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) 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, 0.962
• PP5: Variant 15-48488433-A-G is Pathogenic according to our data. Variant chr15-48488433-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 549131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48488433-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.3143T>C	p.Ile1048Thr	missense_variant	Exon 26 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.3143T>C	p.Ile1048Thr	missense_variant	Exon 25 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.3143T>C	p.Ile1048Thr	missense_variant	Exon 26 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:4

Mar 01, 2021

Centre of Medical Genetics, University of Antwerp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2, PS1, PP4 -

Nov 07, 2017

Center for Medical Genetics Ghent, University of Ghent

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 17, 2021

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FBN1 c.3143T>C (p.Ile1048Thr) variant is a missense variant that has been reported in at least three studies, in which it was found in a heterozygous state in at least nine individuals with neonatal Marfan syndrome (Sureka et al. 2014; Carande et al. 2017; Tognato et al. 2019). When parental samples were available, the variant was identified to be de novo. The p.Ile1048Thr variant is absent from the Genome Aggregation Database (versions 2.1.1. and 3.1.2) in a region of good sequencing coverage, so the variant is presumed to be rare. This variant is located in exon 26, within the region of the gene in which most variants associated with neonatal Marfan syndrome are located (Tognato et al. 2019). Kirschner et al. (2011) showed that the p.Ile1048Thr variant did not affect overall structure of the protein; however, it resulted in increased fragmentation of the protein in the presence of certain proteases, higher susceptibility for degradation by matrix metalloproteases, and impaired heparin binding. Based on the collective evidence, the p.Ile1048Thr variant is classified as pathogenic for Marfan syndrome. -

Aug 01, 2019

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I1048T variant is a known neonatal mutation of MFS (PMID: 19002209) and it has been reported in the ClinVar by other submitters (Variation ID: 549131). Functional studies show a change in protein microfibril formation (PMID: 8884270, 21784848). Additionally, computational results of PolyPhen2, Provean, SIFT show a deleterious/damaging effect. -

not provided Pathogenic:1

Aug 11, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PS3, PM2, PP2, PP4 -

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

Nov 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1048 of the FBN1 protein (p.Ile1048Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 8884270, 21135753, 27625872). In at least one individual the variant was observed to be de novo. This variant is also known as T3276C. ClinVar contains an entry for this variant (Variation ID: 549131). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FBN1 function (PMID: 8884270, 21784848). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.71	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.059	T
Vest4		0.93
MutPred		0.87		Loss of stability (P = 0.0236);
MVP		0.99
MPC		1.6
ClinPred		0.97	D
GERP RS		6.2

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: rs1555398673; hg19: chr15-48780630;