rs878853682

Positions:

• chr15-48600147-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):​c.434G>A​(p.Cys145Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.57

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 17 ACMG points.

• PM1: In a region_of_interest Interaction with MFAP4 (size 210) in uniprot entity FBN1_HUMAN there are 27 pathogenic changes around while only 6 benign (82%) 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, 0.995
• PP5: Variant 15-48600147-C-T is Pathogenic according to our data. Variant chr15-48600147-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 237091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48600147-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.434G>A	p.Cys145Tyr	missense_variant	5/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.434G>A	p.Cys145Tyr	missense_variant	4/65		NP_001393645.1
FBN1	NM_001406717.1	c.434G>A	p.Cys145Tyr	missense_variant	5/9		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.434G>A	p.Cys145Tyr	missense_variant	5/66	1	NM_000138.5	ENSP00000325527	P1
FBN1	ENST00000559133.6	c.434G>A	p.Cys145Tyr	missense_variant, NMD_transcript_variant	5/67	1		ENSP00000453958
FBN1	ENST00000674301.2	c.434G>A	p.Cys145Tyr	missense_variant, NMD_transcript_variant	5/68			ENSP00000501333
FBN1	ENST00000537463.6	c.434G>A	p.Cys145Tyr	missense_variant, NMD_transcript_variant	5/31	5		ENSP00000440294

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458560 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725854

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2018

The p.C145Y variant (also known as c.434G>A), located in coding exon 4 of the FBN1 gene, results from a G to A substitution at nucleotide position 434. The cysteine at codon 145 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #02 domain. This alteration has been detected in individuals with classical Marfan syndrome and/or Marfan-like features (Ware AL et al. Cardiovasc. Pathol. Jun;25:418-22; Howarth R et al. Genet. Test., 2007;11:146-52). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). Internal structural assessment indicates this alteration results in loss of a structural disulfide in EGF domain 2 (Yadin DA. Structure. 2013 Oct;21(10):1743-56). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Apr 09, 2021

PS4, PM1, PM2, PP2, PP3 -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2019

In summary, this variant is not present in population databases, has been reported in affected individuals, and affects a residue crucial for protein stability and function. As a result, this variant has been classified as Pathogenic. This variant affects a cysteine residue located within an epidermal-growth-factor (EGF)–like domain of the FBN1 protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for FBN1 protein structure and stability (PMID: 3495735, 4750422, 16677079). In addition, missense substitutions within the FBN1 EGF-like domains affecting cysteine residues are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant has been reported in several unrelated individuals affected with Marfan syndrome (PMID: 17627385, 12938084, Invitae). ClinVar contains an entry for this variant (Variation ID: 237091). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 145 of the FBN1 protein (p.Cys145Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.97	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-9.0	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Vest4		0.99
MutPred		0.99		Loss of disorder (P = 0.0562);
MVP		0.97
MPC		1.9
ClinPred		1.0	D
GERP RS		6.2

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: rs878853682; hg19: chr15-48892344; COSMIC: COSV57309709;