rs397515754

Positions:

• chr15-48516318-T-A
• chr15-48516318-T-G

Variant summary

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

The NM_000138.5(FBN1):​c.1192A>T​(p.Arg398Ter) 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 (★). Synonymous variant affecting the same amino acid position (i.e. R398R) has been classified as Likely benign. 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: 4.21

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 15-48516318-T-A is Pathogenic according to our data. Variant chr15-48516318-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 42281.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.1192A>T	p.Arg398Ter	stop_gained	11/66	ENST00000316623.10
FBN1	NM_001406716.1	c.1192A>T	p.Arg398Ter	stop_gained	10/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.1192A>T	p.Arg398Ter	stop_gained	11/66	1	NM_000138.5	P1
FBN1	ENST00000559133.6	c.1192A>T	p.Arg398Ter	stop_gained, NMD_transcript_variant	11/67	1
FBN1	ENST00000674301.2	c.1192A>T	p.Arg398Ter	stop_gained, NMD_transcript_variant	11/68
FBN1	ENST00000537463.6	c.636+21393A>T		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Sep 12, 2011

The Arg398X variant in FBN1 has not been previously reported in individuals with clinical features of Marfan syndrome or in large population studies. This nonse nse variant leads to a premature termination codon at position 398, which is pre dicted to lead to a truncated or absent protein. Heterozygous variants causing a loss of function of the FBN1 gene is an established disease mechanism in Marfa n syndrome. In summary, this variant meets our criteria to be classified as path ogenic (http://pcpgm.partners.org/LMM). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	A
Vest4		0.84
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs397515754; hg19: chr15-48808515;