rs1057518909

Variant names:

• chr15-48534098-CTTCA-C
• rs1057518909
• NM_000138.5:c.840_843delTGAA

Variant summary

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

The NM_000138.5(FBN1):​c.840_843delTGAA​(p.Asn280LysfsTer49) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 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 15-48534098-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 rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.840_843delTGAA	p.Asn280LysfsTer49	frameshift_variant	Exon 8 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.840_843delTGAA	p.Asn280LysfsTer49	frameshift_variant	Exon 7 of 65		NP_001393645.1
FBN1	NM_001406717.1	c.840_843delTGAA	p.Asn280LysfsTer18	frameshift_variant	Exon 8 of 9		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.840_843delTGAA	p.Asn280LysfsTer49	frameshift_variant	Exon 8 of 66	1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.840_843delTGAA		non_coding_transcript_exon_variant	Exon 8 of 67	1		ENSP00000453958.2
FBN1	ENST00000674301.2	n.840_843delTGAA		non_coding_transcript_exon_variant	Exon 8 of 68			ENSP00000501333.2
FBN1	ENST00000537463.6	n.636+3609_636+3612delTGAA		intron_variant	Intron 7 of 30	5		ENSP00000440294.2

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

Feb 24, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;