15-48437347-G-C

Variant names:

• chr15-48437347-G-C
• rs112989722
• NM_000138.5:c.6354C>G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000138.5(FBN1):​c.6354C>G​(p.Ile2118Met) 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. I2118I) has been classified 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:3
• Conservation: PhyloP100: -0.700

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 13 ACMG points.

• 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, 0.919
• PP5: Variant 15-48437347-G-C is Pathogenic according to our data. Variant chr15-48437347-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.6354C>G	p.Ile2118Met	missense_variant	Exon 52 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.6354C>G	p.Ile2118Met	missense_variant	Exon 51 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.6354C>G	p.Ile2118Met	missense_variant	Exon 52 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:1

Nov 17, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ile2118Met variant in FBN1 has been reported in 1 individual with Marfan s yndrome (Comeglio 2007) and has been identified as a de novo occurrence by our l aboratory in 1 individual with Marfan syndrome. It was absent from large populat ion studies. Computational prediction tools and conservation analysis do not pro vide strong support for or against an impact to the protein. Additionally, anoth er variant affecting the same nucleotide (p.Ile2118Ile) has been shown to lead t o skipping of exon 51 (Liu 1997), suggesting changes to this nucleotide position may not be tolerated. In summary, although additional studies are required to f ully establish its clinical significance, the p.Ile2118Met variant is likely pat hogenic. -

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

Nov 21, 2017

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The FBN1 c.6354C>G (p.Ile2118Met) variant involves the alteration of a non-conserved nucleotide and 3/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index and p-value, respectively). This variant is absent in 276492 control chromosomes (publication controls and gnomAD). The variant has been reported in 1 individual with Marfan syndrome (Comeglio 2007) and described in ClinVar in a patient with Marfan syndrome as a de novo event. Another variant affecting the same nucleotide, c.6354C>T (p.Ile2118Ile - scored DV by LCA) has been reported and found to cause skipping of exon 52 (PMID: 9241263), 3/5 splicing prediction tools for the variant of interest do predict an impact on splicing. However, these predictions have not been functionally assessed. In addition, a clinical diagnostic laboratory has classified the variant as "likely pathogenic." Taken together, this variant is classified as likely pathogenic. -

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

Oct 03, 2023

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 methionine, which is neutral and non-polar, at codon 2118 of the FBN1 protein (p.Ile2118Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Marfan syndrome (PMID: 17657824; Invitae). ClinVar contains an entry for this variant (Variation ID: 180039). 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 not expected to disrupt FBN1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	16
DANN	Uncertain	1.0
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.54	T
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.84	N
REVEL	Uncertain	0.56
Sift	Benign	0.18	T
Sift4G	Benign	0.13	T
Vest4		0.70
MutPred		0.81		Gain of disorder (P = 0.0362);
MVP		0.98
MPC		0.66
ClinPred		0.54	D
GERP RS		-1.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: -25

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs112989722; hg19: chr15-48729544;