15-48487151-G-C

Position:

• chr15-48487151-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_000138.5(FBN1):​c.3513C>G​(p.Cys1171Trp) 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 (★). Synonymous variant affecting the same amino acid position (i.e. C1171C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 0.330

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]

FBN1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a domain EGF-like 18; calcium-binding (size 41) in uniprot entity FBN1_HUMAN there are 11 pathogenic changes around while only 4 benign (73%) 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, 0.997
• PP5: Variant 15-48487151-G-C is Pathogenic according to our data. Variant chr15-48487151-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 492828.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.3513C>G	p.Cys1171Trp	missense_variant	29/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.3513C>G	p.Cys1171Trp	missense_variant	28/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.3513C>G	p.Cys1171Trp	missense_variant	29/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Marfan syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Oct 19, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -

Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 23, 2016

Variant summary: The FBN1 c.3513C>G (p.Cys1171Trp) variant involves the alteration of a non-conserved nucleotide and results in a replacement of a medium size and polar Cysteine (C) with a large size and aromatic (W) located in the EGF-like #14 domain (ACMG: PM1). Cystein residues of the EGF-like domains of FBN1 are known to be important structural elements due to the ability of the sulfhydryl group to participate in disulfide covalent intramolecular cross-linkage. Additionally, cysteine residues in the EGF-like motif may also be necessary for intermolecular interactions with other fibrillin molecules or with other proteins (Dietz_1992). Consequently, 4/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index) (ACMG: PP3). This variant is absent in 121412 control chromosomes while it was reported in an MFS patient who presented with familial disease and ocular, skeletal, and cardiovascular manifestations indicating causality (ACMG: PM2). Moreover, variants impacting the Cys1171 codon such as p.Cys1171Arg, p.Cys1171Tyr, p.Cys1171Phe, and p.Cys1171X are listed in UMD/ClinVar/HGMD as pathogenic indicating the variant to be located in a mutational hotspot and the clinical importance of the Cys1171 residue (ACMG: PM5). Taken together, this variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	-0.0027
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Uncertain	0.78	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-9.9	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Vest4		0.99
MutPred		0.99		Loss of catalytic residue at C1171 (P = 0.0705);
MVP		0.98
MPC		1.7
ClinPred		1.0	D
GERP RS		-4.7

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: rs775417975; hg19: chr15-48779348;