rs1555398753

Variant names:

• chr15-48489678-GGACCAAACAGTTAAAAACAAAAAGTTCATACTTTTCTAAACAAAGATAATTATATAATTCAGAAAGCAAAAAGTCCATGCTGGGATGATCAAGTAGAGTGCTGAGATCATGAAAATGCATCCTATTTGTCTAAAAAGGGAGGCAATTGGCCATGGAAAACGTAACATTGTACCTTTGAAGAAAGGCTTTCCATT-G
• rs1555398753
• NM_000138.5:c.3061_3082+172del

Variant summary

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

The NM_000138.5(FBN1):​c.3061_3082+172del​(p.Asn1021fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a non-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: 31)
• Consequence: FBN1 NM_000138.5 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.790

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 15-48489678-GGACCAAACAGTTAAAAACAAAAAGTTCATACTTTTCTAAACAAAGATAATTATATAATTCAGAAAGCAAAAAGTCCATGCTGGGATGATCAAGTAGAGTGCTGAGATCATGAAAATGCATCCTATTTGTCTAAAAAGGGAGGCAATTGGCCATGGAAAACGTAACATTGTACCTTTGAAGAAAGGCTTTCCATT-G is Pathogenic according to our data. Variant chr15-48489678-GGACCAAACAGTTAAAAACAAAAAGTTCATACTTTTCTAAACAAAGATAATTATATAATTCAGAAAGCAAAAAGTCCATGCTGGGATGATCAAGTAGAGTGCTGAGATCATGAAAATGCATCCTATTTGTCTAAAAAGGGAGGCAATTGGCCATGGAAAACGTAACATTGTACCTTTGAAGAAAGGCTTTCCATT-G is described in ClinVar as [Pathogenic]. Clinvar id is 457187.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.3061_3082+172del	p.Asn1021fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 25 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.3061_3082+172del	p.Asn1021fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 24 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.3061_3082+172del	p.Asn1021fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 25 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Dec 13, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a large deletion affecting part of exon 25 and extending into intron 25, with one breakpoint at position c.3061 and the other breakpoint at position c.3082+172. This sequence change creates a premature translational stop signal (p.Asn1021Ilefs*7) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FBN1-related disease. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555398753; hg19: chr15-48781875;