chr15-48488433-A-G

Position:

• chr15-48488433-A-G

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1048V) has been classified as Uncertain significance.

• 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 hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.962
• 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/exons	MANE	UniProt
FBN1	NM_000138.5	c.3143T>C	p.Ile1048Thr	missense_variant	26/66	ENST00000316623.10
FBN1	NM_001406716.1	c.3143T>C	p.Ile1048Thr	missense_variant	25/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.3143T>C	p.Ile1048Thr	missense_variant	26/66	1	NM_000138.5	P1

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

Pathogenic, criteria provided, single submitter	clinical testing	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	Aug 01, 2019	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. -
Likely pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PS1, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 17, 2021	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. -
Pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Aug 11, 2019

PS4, PS3, PM2, PP2, PP4 -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2020

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change leads to impaired fibrillin-1 microfibril formation (PMID: 8884270, 21784848). This variant has been reported in several individuals affected with Marfan syndrome at an early age, including one de novo occurrence (PMID: 8884270, 27625872, 21135753). This variant is also described as T3276C in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 1048 of the FBN1 protein (p.Ile1048Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. -

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
MutationTaster	Benign	1.0	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;