rs1555400601

chr15-48520727-C-T

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.1079G>A(p.Cys360Tyr) 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: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.71

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 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FBN1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 15-48520727-C-T is Pathogenic according to our data. Variant chr15-48520727-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 457157.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.1079G>A	p.Cys360Tyr	missense_variant	10/66	ENST00000316623.10
FBN1	NM_001406716.1	c.1079G>A	p.Cys360Tyr	missense_variant	9/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.1079G>A	p.Cys360Tyr	missense_variant	10/66	1	NM_000138.5	P1
FBN1	ENST00000559133.6	c.1079G>A	p.Cys360Tyr	missense_variant, NMD_transcript_variant	10/67	1
FBN1	ENST00000674301.2	c.1079G>A	p.Cys360Tyr	missense_variant, NMD_transcript_variant	10/68
FBN1	ENST00000537463.6	c.636+16984G>A		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 09, 2019

This sequence change replaces cysteine with tyrosine at codon 360 of the FBN1 protein (p.Cys360Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FBN1-related disease. In summary, this variant is a novel missense change affecting a residue crucial for protein stability and function. Although additional genetic data will be necessary to further confirm pathogenicity for this variant, cysteine substitutions located in FBN1 TGFBP domains are likely deleterious. For these reasons, this variant has been classified as Likely Pathogenic. This variant affects a cysteine residue located within a TGFBP domain of the FBN1 protein. Cysteine residues in these domains are believed to be involved in intramolecular disulfide bridges and to be important for FBN1 structure. Although the exact function of the FBN1 TGFBP domains has not being elucidated (PMID: 10930463, 27437668), missense substitutions within the TGFBP domains affecting cysteine residues are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). -

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	0.91
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-9.8	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Vest4		0.96
MutPred		0.98		Gain of loop (P = 0.1069);
MVP		0.99
MPC		1.9
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: rs1555400601; hg19: chr15-48812924;