15-48432905-C-T
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Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2
The NM_000138.5(FBN1):c.6700G>A(p.Val2234Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,613,688 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0012 ( 2 hom. )
Consequence
FBN1
NM_000138.5 missense
NM_000138.5 missense
Scores
5
12
Clinical Significance
Conservation
PhyloP100: 1.10
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 -10 ACMG points.
PM1
In a domain EGF-like 38; calcium-binding (size 40) in uniprot entity FBN1_HUMAN there are 19 pathogenic changes around while only 2 benign (90%) in NM_000138.5
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=0.05713734).
BP6
Variant 15-48432905-C-T is Benign according to our data. Variant chr15-48432905-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36104.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=11, Uncertain_significance=2, Benign=6}. Variant chr15-48432905-C-T is described in Lovd as [Benign]. Variant chr15-48432905-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000742 (113/152268) while in subpopulation AMR AF= 0.00137 (21/15288). AF 95% confidence interval is 0.000941. There are 0 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 113 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FBN1 | NM_000138.5 | c.6700G>A | p.Val2234Met | missense_variant | 55/66 | ENST00000316623.10 | NP_000129.3 | |
| FBN1 | NM_001406716.1 | c.6700G>A | p.Val2234Met | missense_variant | 54/65 | NP_001393645.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FBN1 | ENST00000316623.10 | c.6700G>A | p.Val2234Met | missense_variant | 55/66 | 1 | NM_000138.5 | ENSP00000325527.5 |
Frequencies
GnomAD3 genomes 0.000743 AC: 113AN: 152150Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000777 AC: 195AN: 251034Hom.: 0 AF XY: 0.000796 AC XY: 108AN XY: 135642
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GnomAD4 exome AF: 0.00120 AC: 1756AN: 1461420Hom.: 2 Cov.: 32 AF XY: 0.00117 AC XY: 854AN XY: 727018
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GnomAD4 genome 0.000742 AC: 113AN: 152268Hom.: 0 Cov.: 32 AF XY: 0.000685 AC XY: 51AN XY: 74458
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:22
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Marfan syndrome Benign:7
| Likely benign, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Aug 15, 2016 | Originally interpreted based on literature review PMID: 25637381. Found in patient having exome sequencing for an unrelated indication. No known history of Marfan syndrome. - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Jun 01, 2018 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 23, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Aug 01, 2023 | - - |
| Benign, no assertion criteria provided | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 12, 2015 | - - |
| Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 01, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
not provided Uncertain:1Benign:4
| Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2024 | FBN1: BS1, BS2 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 11, 2017 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 27, 2021 | Reported in ClinVar (ClinVar Variant ID#36104; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 24941995, 17657824, 17663468, 21883168, 25812041, 24055113, 17253931, 32679894) - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 13, 2023 | - - |
not specified Uncertain:1Benign:2
| Benign, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Val2234Met variant in FBN1 has been reported in at least 1 Norwegian and 1 other individual with Marfan Syndrome (PMID: 17663468, 17253931; Lazalde et al. 2017), but has been identified in 0.1281% (165/128814) of European (non-Finnish) chromosomes, 0.09601% (34/35414) of Latino chromosomes, and 0.01602% (4/24966) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs112084407). This variant has also been reported benign, likely benign, and a VUS in ClinVar (Variation ID: 36104). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Val2234Met variant did not segregate with Marfan Syndrome in 4 affected relatives of an individual with the variant, suggesting that this variant is not pathogenic for Marfan Syndrome (PMID: 17663468). Marfan Syndrome has been reported to have high clinical penetrance (PMID: 20301510) and the p.Val2234Met variant has been reported in the literature in at least 4 individuals without Marfan Syndrome, increasing the chance that this variant is benign (PMID: 25812041, 25637381; Variation ID: 36104). Two affected individuals with this variant have an alternative molecular basis for Marfan Syndrome, suggesting that this variant may not be pathogenic (PMID: 17663468; Lazalde et al. 2017). The number of missense variants reported in FBN1 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, this variant meets criteria to be classified as benign for Marfan Syndrome in an autosomal dominant manner based on its frequency in the general population and multiple occurrences in individuals without Marfan Syndrome. ACMG/AMP Criteria applied: BS2, BS4, BS1, BP5 (Richards 2015). - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 01, 2011 | The 6700G>A (Val2234Met) variant has been reported in the literature in one indi vidual meeting the Ghent clinical criteria for Marfan syndrome (Tjeldhorn 2006, Rand-Hendriksen 2007). However, this individual also carried a second FBN1 varia nt (Asp1113Gly) that was found in four affected family members and who were all negative for the Val2234Met variant (Rand-Hendriksen 2007). This variant has bee n identified by our laboratory in one family; two family members that are report edly minimally affected with some clinical features of Marfan syndrome carry thi s variant. Valine (Val) at amino acid position 2234 is not completely conserved in other mammals or distantly related species (cow, dog, elephant, chicken and f rog carry an alanine; opossum carries an isoleucine; fish carries a threonine). Furthermore, this variant has been reported in dbSNP (rs112084407) with a minor allele frequency of 0.002. Collectively, these data reduce the likelihood that t his change is pathogenic. However, in the absence of additional data, we cannot conclusively determine the clinical significance of this variant at this time, t hough we lean towards a likely benign role. - |
| Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Familial thoracic aortic aneurysm and aortic dissection Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 26, 2018 | - - |
| Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 22, 2018 | - - |
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 29, 2014 | 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. - |
Geleophysic dysplasia Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 01, 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Acromicric dysplasia Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 01, 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
FBN1-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 10, 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 29, 2024 | - - |
Ectopia lentis 1, isolated, autosomal dominant Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 01, 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Connective tissue disorder Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
T
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Vest4
MVP
MPC
ClinPred
T
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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