rs1057518909

chr15-48534098-CTTCA-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_000138.5(FBN1):c.840_843del(p.Asn280LysfsTer49) variant causes a frameshift change involving the alteration of a conserved nucleotide. 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 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02

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 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 15-48534098-CTTCA-C is Pathogenic according to our data. Variant chr15-48534098-CTTCA-C is described in ClinVar as [Pathogenic]. Clinvar id is 374115.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.840_843del	p.Asn280LysfsTer49	frameshift_variant	8/66	ENST00000316623.10
FBN1	NM_001406716.1	c.840_843del	p.Asn280LysfsTer49	frameshift_variant	7/65
FBN1	NM_001406717.1	c.840_843del	p.Asn280LysfsTer18	frameshift_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.840_843del	p.Asn280LysfsTer49	frameshift_variant	8/66	1	NM_000138.5	P1
FBN1	ENST00000559133.6	c.840_843del	p.Asn280LysfsTer49	frameshift_variant, NMD_transcript_variant	8/67	1
FBN1	ENST00000537463.6	c.636+3609_636+3612del		intron_variant, NMD_transcript_variant		5
FBN1	ENST00000674301.2	c.840_843del	p.Asn280LysfsTer49	frameshift_variant, NMD_transcript_variant	8/68

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inguinal hernia;C0027092:Myopia;C0241240:Tall stature;C1844820:Joint hypermobility;C2051831:Pectus excavatum Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Feb 24, 2015

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Computational scores

Source: dbNSFP v4.3

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: rs1057518909; hg19: chr15-48826295;