rs1555395226

Positions:

• chr15-48437354-C-G
• chr15-48437354-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The ENST00000316623.10(FBN1):​c.6347G>C​(p.Gly2116Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2116E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 ENST00000316623.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.32

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in ENST00000316623.10
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.6347G>C	p.Gly2116Ala	missense_variant	52/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.6347G>C	p.Gly2116Ala	missense_variant	51/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.6347G>C	p.Gly2116Ala	missense_variant	52/66	1	NM_000138.5	ENSP00000325527	P1
FBN1	ENST00000559133.6	c.6347G>C	p.Gly2116Ala	missense_variant, NMD_transcript_variant	52/67	1		ENSP00000453958
FBN1	ENST00000674301.2	c.6347G>C	p.Gly2116Ala	missense_variant, NMD_transcript_variant	52/68			ENSP00000501333
FBN1	ENST00000537463.6	c.*2110G>C		3_prime_UTR_variant, NMD_transcript_variant	27/31	5		ENSP00000440294

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 14, 2017

This sequence change replaces glycine with alanine at codon 2116 of the FBN1 protein (p.Gly2116Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual affected with aortic root dilatation and pneumothorax (PMID: 25652356). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	0.44	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.66
Sift	Benign	0.091	T
Sift4G	Uncertain	0.019	D
Vest4		0.31
MutPred		0.81		Loss of glycosylation at S2115 (P = 0.0391);
MVP		0.97
MPC		0.71
ClinPred		0.91	D
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1555395226; hg19: chr15-48729551;