rs397515830

Positions:

• chr15-48441765-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):​c.6119G>A​(p.Cys2040Tyr) 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. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.90

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 15 ACMG points.

• 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 15-48441765-C-T is Pathogenic according to our data. Variant chr15-48441765-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48441765-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.6119G>A	p.Cys2040Tyr	missense_variant	50/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.6119G>A	p.Cys2040Tyr	missense_variant	49/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.6119G>A	p.Cys2040Tyr	missense_variant	50/66	1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PVS2, PP4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 15, 2010	The 6119G>A (Cys2040Tyr) variant has not been previously reported in the literat ure or been identified by our laboratory. This variant affects a cysteine residu e; cysteine substitutions are a common finding in individuals with Marfan syndro me (Schrijver 1999). Cysteine at amino acid position 2040 is highly conserved ac ross evolutionarily distinct species. In addition, computational analyses (PolyP hen, SIFT, AlignGVGD) suggest that the Cys2040Tyr variant may impact the normal function of the protein, although it should be noted that the sensitivity and sp ecificity of these analyses has not been determined. This variant is likely to b e pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.96	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-9.5	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.020	D
Vest4		0.99
MutPred		0.98		Loss of ubiquitination at K2037 (P = 0.0502);
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.9

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: rs397515830; hg19: chr15-48733962;