rs764827921

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PP2PP3_ModerateBS2

The NM_000138.5(FBN1):​c.2093C>T​(p.Pro698Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P698S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

FBN1
NM_000138.5 missense

Scores

9
3
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 10.0
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1
In a domain TB 3 (size 52) in uniprot entity FBN1_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_000138.5
PP2
Missense variant in the FBN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 1311 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.0644 (above the threshold of 3.09). Trascript score misZ: 8.1787 (above the threshold of 3.09). GenCC associations: The gene is linked to MASS syndrome, Weill-Marchesani syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, Acromicric dysplasia, familial thoracic aortic aneurysm and aortic dissection, progeroid and marfanoid aspect-lipodystrophy syndrome, ectopia lentis 1, isolated, autosomal dominant, Marfan syndrome, Weill-Marchesani syndrome 2, dominant, isolated ectopia lentis, neonatal Marfan syndrome, stiff skin syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.912
BS2
High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBN1NM_000138.5 linkc.2093C>T p.Pro698Leu missense_variant Exon 17 of 66 ENST00000316623.10 NP_000129.3 P35555
FBN1NM_001406716.1 linkc.2093C>T p.Pro698Leu missense_variant Exon 16 of 65 NP_001393645.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBN1ENST00000316623.10 linkc.2093C>T p.Pro698Leu missense_variant Exon 17 of 66 1 NM_000138.5 ENSP00000325527.5 P35555

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152194
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251364
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135838
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461658
Hom.:
0
Cov.:
32
AF XY:
0.0000151
AC XY:
11
AN XY:
727118
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152194
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000386
Hom.:
0
Bravo
AF:
0.0000151
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:2
Oct 12, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces proline with leucine at codon 698 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with thoracic aortic aneurysm and dissection, who showed no features of Marfan syndrome and lacked family history of Marfan syndrome (PMID: 26621581). This variant has been identified in 4/282774 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Aug 14, 2015
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.P698L variant (also known as c.2093C>T), located in coding exon 16 of the FBN1 gene, results from a C to T substitution at nucleotide position 2093. The proline at codon 698 is replaced by leucine, an amino acid with a few similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6493 samples (12986 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Marfan syndrome Uncertain:1
Sep 23, 2024
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces proline with leucine at codon 698 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with thoracic aortic aneurysm and dissection, who showed no features of Marfan syndrome and lacked family history of Marfan syndrome (PMID: 26621581). This variant has been identified in 4/282774 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:1
Oct 26, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: FBN1 c.2093C>T (p.Pro698Leu) results in a non-conservative amino acid change located in the TB domain (IPR017878) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251364 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2093C>T has been reported in the literature in an individual affected with a type A dissection, ascending aortic dilatation and other risk factors (bicuspid aortic valve and hypertension). But the variant did not segregate with aortic disease (Regalado_2016). This report however, does not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1
Sep 22, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Identified in a patient with Type A aortic dissection in the published literature (Regalado et al., 2015); however, this patient had other risk factors for dissection including bicuspid aortic valve and hypertension and the authors report this variant did not segregate with aortic disease; Not observed at significant frequency in large population cohorts (gnomAD); Does not affect a cysteine residue within a calcium-binding EGF-like domain or a TGF-binding protein domain of the FBN1 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12938084, 26621581) -

Acute aortic dissection;C0345050:Congenital aneurysm of ascending aorta Benign:1
Jan 20, 2016
University of Washington Center for Mendelian Genomics, University of Washington
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: research

- -

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1
Apr 25, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.33
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
32
DANN
Uncertain
1.0
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.85
D
M_CAP
Pathogenic
0.38
D
MetaRNN
Pathogenic
0.91
D
MetaSVM
Uncertain
0.63
D
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-5.7
D
REVEL
Pathogenic
0.69
Sift
Benign
0.22
T
Sift4G
Benign
0.087
T
Vest4
0.85
MVP
0.93
MPC
2.2
ClinPred
0.90
D
GERP RS
6.1

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs764827921; hg19: chr15-48796004; COSMIC: COSV57311884; API