rs111801777
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP5BS1BP2
This summary comes from the ClinGen Evidence Repository: The NM_000138 c.3058A>G, is a missense variant in FBN1 predicted to cause a substitution of a Threonine by Alanine at amino acid 1020 (p.Thr1020Ala). This variant was found in 12 probands with variable phenotypes, mostly thoracic aortic aneurysm or a marfanoid habitus. One proband additionally presented ectopia lentis. Two of these probands carried two other pathogenic variants: a variant in FBN1 (BP2) and a variant in TGFBR1 (BP5). The variant in FBN1 has been reported ten times in ClinVar: 8 times as likely benign and two times as a variant of uncertain significance (Variation ID: 42325). The variant has been reported in the literature in multiple affected individuals including one individual with classical Marfan syndrome (PMID:11175294), one individual with incomplete Marfan syndrome (PMID:18435798), one patient with MASS syndrome (PMID:25944730), and an individual with bicuspid aortic valve and aortic root aneurysm (PMID:28387797). This variant has also been reported in 3 patients with Lujan-Fryns syndrome (PMID:19293843, PMID:28027854), including two brothers with marfanoid habitus, learning disabilities without cardiac defects (PMID:28027854). These brothers also share a variant in MECP2. Segregation analysis in one family showed that the variant was also present in four additional family members, none of which had aortic aneurysm, two had a marfanoid habitus This variant has been identified in 80 individuals of European-non-Finnish origin (MAF: 0.062%) in gnomad v2.1.1 (https://gnomad.broadinstitute.org/) (BS1). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of benign arguments PP2 cannot be used. In summary, this variant meets criteria to be classified as likely benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS1, BP2, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA013721/MONDO:0007947/022
Frequency
Genomes: 𝑓 0.00033 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00033 ( 1 hom. )
Consequence
FBN1
NM_000138.5 missense
NM_000138.5 missense
Scores
4
13
Clinical Significance
Conservation
PhyloP100: 1.49
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 Likely_benign. Variant got -6 ACMG points.
BP2
For more information check the summary or visit ClinGen Evidence Repository.
BP5
For more information check the summary or visit ClinGen Evidence Repository.
BS1
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FBN1 | NM_000138.5 | c.3058A>G | p.Thr1020Ala | missense_variant | 25/66 | ENST00000316623.10 | NP_000129.3 | |
| FBN1 | NM_001406716.1 | c.3058A>G | p.Thr1020Ala | missense_variant | 24/65 | NP_001393645.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FBN1 | ENST00000316623.10 | c.3058A>G | p.Thr1020Ala | missense_variant | 25/66 | 1 | NM_000138.5 | ENSP00000325527.5 |
Frequencies
GnomAD3 genomes 0.000335 AC: 51AN: 152204Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000454 AC: 114AN: 251294Hom.: 0 AF XY: 0.000442 AC XY: 60AN XY: 135818
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GnomAD4 exome AF: 0.000330 AC: 482AN: 1461856Hom.: 1 Cov.: 31 AF XY: 0.000355 AC XY: 258AN XY: 727226
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GnomAD4 genome 0.000335 AC: 51AN: 152322Hom.: 0 Cov.: 31 AF XY: 0.000322 AC XY: 24AN XY: 74472
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ClinVar
Significance: Likely benign
Submissions summary: Uncertain:3Benign:12
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Marfan syndrome Uncertain:1Benign:4
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Center for Medical Genetics Ghent, University of Ghent | Nov 07, 2017 | - - |
| Likely benign, reviewed by expert panel | curation | ClinGen FBN1 Variant Curation Expert Panel, ClinGen | Dec 01, 2022 | The NM_000138 c.3058A>G, is a missense variant in FBN1 predicted to cause a substitution of a Threonine by Alanine at amino acid 1020 (p.Thr1020Ala). This variant was found in 12 probands with variable phenotypes, mostly thoracic aortic aneurysm or a marfanoid habitus. One proband additionally presented ectopia lentis. Two of these probands carried two other pathogenic variants: a variant in FBN1 (BP2) and a variant in TGFBR1 (BP5). The variant in FBN1 has been reported ten times in ClinVar: 8 times as likely benign and two times as a variant of uncertain significance (Variation ID: 42325). The variant has been reported in the literature in multiple affected individuals including one individual with classical Marfan syndrome (PMID: 11175294), one individual with incomplete Marfan syndrome (PMID: 18435798), one patient with MASS syndrome (PMID: 25944730), and an individual with bicuspid aortic valve and aortic root aneurysm (PMID: 28387797). This variant has also been reported in 3 patients with Lujan-Fryns syndrome (PMID: 19293843, PMID: 28027854), including two brothers with marfanoid habitus, learning disabilities without cardiac defects (PMID: 28027854). These brothers also share a variant in MECP2. Segregation analysis in one family showed that the variant was also present in four additional family members, none of which had aortic aneurysm, two had a marfanoid habitus This variant has been identified in 80 individuals of European-non-Finnish origin (MAF: 0.062%) in gnomad v2.1.1 (https://gnomad.broadinstitute.org/) (BS1). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of benign arguments PP2 cannot be used. In summary, this variant meets criteria to be classified as likely benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS1, BP2, BP5. - |
| Likely benign, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 27, 2024 | - - |
not provided Uncertain:2Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | FBN1: BP4, BS1 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 08, 2017 | The T1020A variant of uncertain significance in the FBN1 gene has been reported previously in association with Marfan syndrome (both classic and incomplete presentations), MASS syndrome, and Lujan-Fryns syndrome (Tiecke et al., 2001; Attanasio et al., 2008; Wooderchak-Donahue et al., 2015; Stheneur et al., 2009; Groth et al., 2015). The T1020A variant has also been identified in an individual with bicuspid aortic valve and aortic root aneurysm, yet no additional manifestations of Marfan syndrome (Girdauskas et al., 2017). Giorgio et al. (2016) reported a consanguineous family in which both the T1020A variant, as well as a variant in the MECP2 gene, were identified in two brothers with intellectual disability and Marfanoid habitus; both variants were absent in a healthy third brother. While the MECP2 variant was inherited from the mother (who showed a skewed X-inactivation pattern), the T1020A variant was inherited from the unaffected father (Giorgio et al., 2016). T1020A was reported in an individual with sudden death and hypertrophic cardiomyopathy identified on autopsy; variants in several other cardiac genes were also found (Sanchez et al., 2016). Although T1020A has been identified in several unrelated individuals referred for Marfan/TAAD testing at GeneDx, observation in these individuals, for whom segregation data is lacking, is not sufficient to determine the absolute pathogenicity of this variant. The T1020A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Furthermore, the T1020A variant does not affect a cysteine residue within a calcium-binding EGF-like 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). Finally, T1020A was observed in 79/126,548 (0.06%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Let et al., 2016). - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 21, 2022 | - - |
Familial thoracic aortic aneurysm and aortic dissection Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 28, 2019 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 26, 2017 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 24, 2019 | - - |
not specified Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Blueprint Genetics | Oct 27, 2015 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 18, 2019 | The p.Thr1020Ala variant in FBN1 is classified as likely benign because it has been identified in 0.06% (80/129022) of European chromosomes in gnomAD (http://gnomad.broadinstitute.org). It has also been reported in 2 individuals with Marfan syndrome (Tiecke 2001, Attanasio 2008), 1 individual with MASS phenotype (Wooderchak-Donahue, 2014), and in 2 individuals with Lujan-Fryns syndrome (Stheneur 2009, Giorgio 2017), one of whom inherited the FBN1 variant from his unaffected father and also carried a MECP2 variant. ACMG/AMP Criteria applied: BS1, BP4, BP5. - |
FBN1-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 02, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
D
Sift4G
Benign
T
Vest4
MVP
MPC
ClinPred
T
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at