rs1064793637

chr15-48526200-GT-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000138.5(FBN1):c.917del(p.Asn306ThrfsTer24) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. N306N) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.95

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]

LOC124903488 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 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 15-48526200-GT-G is Pathogenic according to our data. Variant chr15-48526200-GT-G is described in ClinVar as [Pathogenic]. Clinvar id is 419091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.917del	p.Asn306ThrfsTer24	frameshift_variant	9/66	ENST00000316623.10
FBN1	NM_001406716.1	c.917del	p.Asn306ThrfsTer24	frameshift_variant	8/65
LOC124903488	XR_007064628.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.917del	p.Asn306ThrfsTer24	frameshift_variant	9/66	1	NM_000138.5	P1
FBN1	ENST00000559133.6	c.917del	p.Asn306ThrfsTer24	frameshift_variant, NMD_transcript_variant	9/67	1
FBN1	ENST00000674301.2	c.917del	p.Asn306ThrfsTer24	frameshift_variant, NMD_transcript_variant	9/68
FBN1	ENST00000537463.6	c.636+11510del		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 01, 2017

The c.917delA variant in the FBN1 gene has been reported previously in one individual with suspectedMarfan syndrome (Magyar I et al., 2009). The c.917delA deletion is expected to result in either anabnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNAdecay. Other frameshift variants in the FBN1 gene have been reported in the Human Gene MutationDatabase in association with Marfan syndrome (Stenson P et al., 2014). Furthermore, the c.917delA deletion was not observed in approximately 6,500 individuals of European and African American ancestry in theNHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, c.917delA in the FBN1 gene is interpreted as a pathogenic variant. -

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 17, 2017

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in FBN1 are known to be pathogenic. This particular variant has been reported in the literature in an individual with Marfan syndrome (PMID: 19618372). This sequence change deletes 1 nucleotide from exon 9 of the FBN1 mRNA (c.917delA), causing a frameshift at codon 306. This creates a premature translational stop signal (p.Asn306Thrfs*24) and is expected to result in an absent or disrupted protein product. -

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: rs1064793637; hg19: chr15-48818397;