rs112287730
Positions:
Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBS1BS2
The ENST00000316623.10(FBN1):c.2956G>A(p.Ala986Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0011 in 1,614,124 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A986V) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.0010 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0011 ( 5 hom. )
Consequence
FBN1
ENST00000316623.10 missense
ENST00000316623.10 missense
Scores
1
10
6
Clinical Significance
Conservation
PhyloP100: 3.94
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 Benign. Variant got -17 ACMG points.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in ENST00000316623.10
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN1. . Gene score misZ 5.0644 (greater than the threshold 3.09). Trascript score misZ 8.1787 (greater than threshold 3.09). GenCC has associacion of gene with 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.06246361).
BP6
Variant 15-48489977-C-T is Benign according to our data. Variant chr15-48489977-C-T is described in ClinVar as [Benign]. Clinvar id is 36060.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr15-48489977-C-T is described in Lovd as [Likely_benign]. Variant chr15-48489977-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00104 (159/152234) while in subpopulation NFE AF= 0.00178 (121/68020). AF 95% confidence interval is 0.00152. There are 0 homozygotes in gnomad4. There are 73 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 159 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FBN1 | NM_000138.5 | c.2956G>A | p.Ala986Thr | missense_variant | 25/66 | ENST00000316623.10 | NP_000129.3 | |
| FBN1 | NM_001406716.1 | c.2956G>A | p.Ala986Thr | missense_variant | 24/65 | NP_001393645.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FBN1 | ENST00000316623.10 | c.2956G>A | p.Ala986Thr | missense_variant | 25/66 | 1 | NM_000138.5 | ENSP00000325527 | P1 |
Frequencies
GnomAD3 genomes 0.00105 AC: 159AN: 152116Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00118 AC: 297AN: 251462Hom.: 0 AF XY: 0.00131 AC XY: 178AN XY: 135910
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GnomAD4 exome AF: 0.00111 AC: 1617AN: 1461890Hom.: 5 Cov.: 31 AF XY: 0.00116 AC XY: 841AN XY: 727246
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GnomAD4 genome 0.00104 AC: 159AN: 152234Hom.: 0 Cov.: 31 AF XY: 0.000981 AC XY: 73AN XY: 74442
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ClinVar
Significance: Benign
Submissions summary: Uncertain:3Benign:26
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Marfan syndrome Uncertain:1Benign:6
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Benign, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Jul 09, 2015 | - - |
| Likely benign, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Mar 11, 2015 | - - |
| Benign, reviewed by expert panel | curation | ClinGen FBN1 Variant Curation Expert Panel, ClinGen | Sep 26, 2023 | NM_000138.5 c.2956G>A is a missense variant in FBN1 predicted to cause a substitution of an alanine by a threonine at amino acid 986 (p.Ala986Thr). This variant has been identified in numerous individuals with diagnoses or suspicion of Marfan syndrome in both the published literature and internal databases (PP4; PMIDs: 24793577, 26410935, 27582083, 28679693, 28387797; Bichat, Mayo, UZG, UZA); however, in at least 3 of these cases, another pathogenic variant in FBN1 was also present (BP2; Bichat). This variant has been previously reported in ClinVar as likely benign or benign by more than 20 laboratories (Variation ID: 36060). It is present in gnomAD v2.1.1 at a frequency of 0.19% (245/129170 alleles) in the European sub-population (BA1; https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis are unclear about a predicted impact of this variant. In summary, this variant meets criteria to be classified as benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BA1, BP2, PP4. The pathogenic evidence code PP4 was not considered to be in conflict with this conclusion. - |
| Uncertain significance, no assertion criteria provided | clinical testing | Center for Medical Genetics Ghent, University of Ghent | Nov 07, 2017 | - - |
| Benign, no assertion criteria provided | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 13, 2012 | - - |
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:2Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 16, 2018 | - - |
| Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 16, 2017 | - - |
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 18, 2015 | This alteration is classified as 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
| Uncertain significance, no assertion criteria provided | clinical testing | Blueprint Genetics | Dec 27, 2013 | - - |
not provided Benign:4
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | FBN1: BS1 - |
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 28, 2020 | This variant is associated with the following publications: (PMID: 16220557, 24793577, 12402346, 19370756, 27582083, 26410935, 28387797, 23608731, 28679693) - |
| Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
not specified Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 02, 2014 | p.Ala986Thr in exon 25 of FBN1: This variant is not expected to have clinical si gnificance because it has been identified in 0.198% (134/67678) of non-Finnish E uropean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad institute.org; dbSNP rs112287730). This variant has been reported in 5 individua ls with clinical features of Marfan syndrom and/or connective tissue disorder, b ut was also identified in 2 unaffected relatives from two families (Rommel 2002, Frederic 2009, Aboni 2013, Lerner-Ellis 2014). - |
| Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 15, 2016 | - - |
Connective tissue disorder Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 01, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Acromicric dysplasia Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
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 29, 2024 | - - |
Marfan syndrome;C0265287:Acromicric dysplasia;C1858556:MASS syndrome;C1861456:Stiff skin syndrome;C1869115:Weill-Marchesani syndrome 2, dominant;C3280054:Geleophysic dysplasia 2;C3541518:Ectopia lentis 1, isolated, autosomal dominant;C4310796:Progeroid and marfanoid aspect-lipodystrophy syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | FBN1 NM_000138.4 exon 25 p.Ala986Thr (c.2956G>A): This variant has been reported in the literature in at least 4 individuals with features of connective tissues disorders (Lerner-Ellis 2014 PMID:24793577, Arnaud 2017 PMID:27582083, Cousin 2017 PMID:28679693, Girdauskas 2017 PMID:28387797). However, this variant is also present in 0.1% (20/10474) of Finnish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-48489977-C-T?dataset=gnomad_r3) and is present in ClinVar, with several labs classifying this variant as benign or likely benign (Variation ID:36060). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign. - |
Stiff skin syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
Weill-Marchesani syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
Geleophysic dysplasia Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
FBN1-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 12, 2020 | 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). - |
Ectopia lentis 1, isolated, autosomal dominant Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N
REVEL
Uncertain
Sift
Benign
T
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