rs137854462

Positions:

• chr15-48510115-T-A

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.1643A>T​(p.Asn548Ile) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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, 0.995
• PP5: Variant 15-48510115-T-A is Pathogenic according to our data. Variant chr15-48510115-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 16432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48510115-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.1643A>T	p.Asn548Ile	missense_variant	14/66	ENST00000316623.10
FBN1	NM_001406716.1	c.1643A>T	p.Asn548Ile	missense_variant	13/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.1643A>T	p.Asn548Ile	missense_variant	14/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 21, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 20, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FBN1 function (PMID: 21784848). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 16432). This variant is also known as p.Asn351Ile. This missense change has been observed in individual(s) with Marfan syndrome (PMID: 8406497). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 548 of the FBN1 protein (p.Asn548Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	30
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-8.4	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.97
MutPred		0.98		Loss of disorder (P = 0.0622);
MVP		0.97
MPC		2.4
ClinPred		1.0	D
GERP RS		5.5

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: rs137854462; hg19: chr15-48802312;