rs363853

Positions:

• chr15-48596292-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000138.5(FBN1):​c.529T>C​(p.Cys177Arg) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C177S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.95

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.

• PM1: In a domain EGF-like 3 (size 31) in uniprot entity FBN1_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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). The gene has 1311 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. GenCC has associacion of the 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 15-48596292-A-G is Pathogenic according to our data. Variant chr15-48596292-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42380.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-48596292-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.529T>C	p.Cys177Arg	missense_variant	6/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.529T>C	p.Cys177Arg	missense_variant	5/65		NP_001393645.1
FBN1	NM_001406717.1	c.529T>C	p.Cys177Arg	missense_variant	6/9		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.529T>C	p.Cys177Arg	missense_variant	6/66	1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.529T>C		non_coding_transcript_exon_variant	6/67	1		ENSP00000453958.2
FBN1	ENST00000537463.6	n.529T>C		non_coding_transcript_exon_variant	6/31	5		ENSP00000440294.2
FBN1	ENST00000674301.2	n.529T>C		non_coding_transcript_exon_variant	6/68			ENSP00000501333.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Marfan syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 04, 2012

The p.Cys177Arg variant in FBN1 has been reported as a de novo change in 2 indiv iduals, a 4 year old individual with isolated ectopia lentis and an individual r eferred for aortopathy genetc testing (Arbustini 2005, Yang 2016). It was also i dentified in 1 individual with a clinical diagnosis of Marfan syndrome (LMM data ). In addition, two different amino acid changes have been reported at the same residue (p.Cys177Ser and p.Cys177Tyr) in two individuals with clinical features of Marfan syndrome (Attanasio 2008), suggesting that changes at this position ma y not be tolerated. This variant impacts a cysteine residue and cysteine substit utions in the calcium-binding EGF-like domains represent the majority of pathoge nic missense changes associated with Marfan syndrome. Computational prediction t ools and conservation analysis are consistent with pathogenicity. In summary, al though additional studies are required to fully establish its clinical significa nce, the p.Cys177Arg variant is likely pathogenic. ACMG/AMP Criteria applied: PM 1, PM2, PM6, PP3, PS4_Supporting. -

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	32
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.89	D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Vest4		0.99
MutPred		0.97		Gain of disorder (P = 0.0281);
MVP		1.0
MPC		1.5
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: rs363853; hg19: chr15-48888489;