rs1555398753

chr15-48489678-GGACCAAACAGTTAAAAACAAAAAGTTCATACTTTTCTAAACAAAGATAATTATATAATTCAGAAAGCAAAAAGTCCATGCTGGGATGATCAAGTAGAGTGCTGAGATCATGAAAATGCATCCTATTTGTCTAAAAAGGGAGGCAATTGGCCATGGAAAACGTAACATTGTACCTTTGAAGAAAGGCTTTCCATT-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PP5_Moderate

The NM_000138.5(FBN1):c.3061_3082+172del variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. N1021N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FBN1 NM_000138.5 splice_donor, splice_donor_5th_base, coding_sequence, 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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.026346333 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• 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/exons	MANE	UniProt
FBN1	NM_000138.5	c.3061_3082+172del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	25/66	ENST00000316623.10
FBN1	NM_001406716.1	c.3061_3082+172del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	24/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.3061_3082+172del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	25/66	1	NM_000138.5	P1

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 13, 2017

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;