rs397515755

Positions:

• chr15-48520711-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000138.5(FBN1):​c.1095C>A​(p.Cys365*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.77

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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-48520711-G-T is Pathogenic according to our data. Variant chr15-48520711-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 42282.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-48520711-G-T is described in Lovd as [Pathogenic]. Variant chr15-48520711-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.1095C>A	p.Cys365*	stop_gained	10/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.1095C>A	p.Cys365*	stop_gained	9/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.1095C>A	p.Cys365*	stop_gained	10/66	1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.1095C>A		non_coding_transcript_exon_variant	10/67	1		ENSP00000453958.2
FBN1	ENST00000674301.2	n.1095C>A		non_coding_transcript_exon_variant	10/68			ENSP00000501333.2
FBN1	ENST00000537463.6	n.636+17000C>A		intron_variant		5		ENSP00000440294.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Marfan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 04, 2015

The p.Cys365X variant in FBN1 has been reported in 1 Caucasian adult with Marfan syndrome (Lerner-Ellis 2014, LMM published data) and segregated with disease in 1 affected relative. It was absent from large population studies (dbSNP rs39751 5755). This nonsense variant leads to a premature termination codon at position 365, which is predicted to lead to a truncated or absent protein. Heterozygous l oss-of-function of the FBN1 gene is associated with Marfan syndrome. In summary, the p.Cys365X variant meets our criteria to be classified as pathogenic for Mar fan syndrome in an autosomal dominant manner based upon predicted impact to the protein and absence from controls. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.94
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: rs397515755; hg19: chr15-48812908;