rs397515753

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000138.5(FBN1):​c.1051C>T​(p.Gln351Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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 stop_gained

Scores

5
1
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 5.19
Variant links:
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]

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ACMG classification

Classification made for transcript

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 15-48520755-G-A is Pathogenic according to our data. Variant chr15-48520755-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 42280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FBN1NM_000138.5 linkuse as main transcriptc.1051C>T p.Gln351Ter stop_gained 10/66 ENST00000316623.10 NP_000129.3
FBN1NM_001406716.1 linkuse as main transcriptc.1051C>T p.Gln351Ter stop_gained 9/65 NP_001393645.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FBN1ENST00000316623.10 linkuse as main transcriptc.1051C>T p.Gln351Ter stop_gained 10/661 NM_000138.5 ENSP00000325527 P1
FBN1ENST00000559133.6 linkuse as main transcriptc.1051C>T p.Gln351Ter stop_gained, NMD_transcript_variant 10/671 ENSP00000453958
FBN1ENST00000674301.2 linkuse as main transcriptc.1051C>T p.Gln351Ter stop_gained, NMD_transcript_variant 10/68 ENSP00000501333
FBN1ENST00000537463.6 linkuse as main transcriptc.636+16956C>T intron_variant, NMD_transcript_variant 5 ENSP00000440294

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
LINK: link

Submissions by phenotype

Marfan syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineSep 13, 2012The Gln351X variant in FBN1 has been reported in one individual with clinical fe atures of Marfan syndrome (Comeglio 2007). This nonsense variant leads to a prem ature termination codon at position 351, which is predicted to lead to a truncat ed or absent protein. Heterozygous loss of function of the FBN1 gene is an estab lished disease mechanism in Marfan syndrome. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). -
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 06, 2023For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 42280). This premature translational stop signal has been observed in individuals with Marfan syndrome (PMID: 17657824, 24199744). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln351*) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
41
DANN
Uncertain
1.0
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.98
D
MutationTaster
Benign
1.0
A
Vest4
0.95
GERP RS
5.7

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397515753; hg19: chr15-48812952; API