rs61746008
Positions:
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_000138.5(FBN1):c.8176C>T(p.Arg2726Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000756 in 1,614,164 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign 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. R2726Q) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.00071 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00076 ( 2 hom. )
Consequence
FBN1
NM_000138.5 missense
NM_000138.5 missense
Scores
2
7
8
Clinical Significance
Conservation
PhyloP100: 2.13
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 -12 ACMG points.
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=0.04389882).
BP6
Variant 15-48412619-G-A is Benign according to our data. Variant chr15-48412619-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16445.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=19, Uncertain_significance=3}. Variant chr15-48412619-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000709 (108/152284) while in subpopulation AMR AF= 0.00209 (32/15298). AF 95% confidence interval is 0.00152. There are 0 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 108 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FBN1 | NM_000138.5 | c.8176C>T | p.Arg2726Trp | missense_variant | 65/66 | ENST00000316623.10 | NP_000129.3 | |
| FBN1 | NM_001406716.1 | c.8176C>T | p.Arg2726Trp | missense_variant | 64/65 | NP_001393645.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FBN1 | ENST00000316623.10 | c.8176C>T | p.Arg2726Trp | missense_variant | 65/66 | 1 | NM_000138.5 | ENSP00000325527 | P1 |
Frequencies
GnomAD3 genomes 0.000710 AC: 108AN: 152166Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000728 AC: 183AN: 251466Hom.: 1 AF XY: 0.000751 AC XY: 102AN XY: 135906
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GnomAD4 exome AF: 0.000761 AC: 1113AN: 1461880Hom.: 2 Cov.: 32 AF XY: 0.000758 AC XY: 551AN XY: 727240
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GnomAD4 genome 0.000709 AC: 108AN: 152284Hom.: 0 Cov.: 33 AF XY: 0.000658 AC XY: 49AN XY: 74460
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:19
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Marfan syndrome Uncertain:4Benign:4
| Uncertain significance, no assertion criteria provided | clinical testing | Center for Medical Genetics Ghent, University of Ghent | Nov 07, 2017 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Apr 19, 2016 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jun 24, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are associated with Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (PMID: 20301510). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have been reported infrequently (PMID: 27274304; 31950671). 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of DISEASE. (SB) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2 & v3: 12 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. p.(Arg2726Leu) and p.(Arg2726Gln) have been reported VUS in ClinVar, but p.(Arg2726Gln) has also been regarded likely benign (PMID: 31227806). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been reported both as VUS and likely benign in ClinVar and it used to be known as a Marfanoid Skeletal Syndrome variant, as it has mostly been detected in individuals without cardiac and ocular manifestations (OMIM). More recently, even though some consider it causative with incomplete penetrance (PMID: 26875674), others see it as a likely benign variant (PMID: 31227806). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Studies have shown that it affects the conversion mediated of profibrillin to fibrillin (PMIDs: 26875674, 7738200). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 28, 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This mutation has been previously reported as causing Marfanoid-like features. It has been found 13 times in our laboratory, always inherited when parents are tested, and not always in patients with Marfanoid features. - |
| Uncertain significance, no assertion criteria provided | literature only | OMIM | Jan 01, 2009 | - - |
| Likely benign, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Dec 01, 2015 | - - |
not provided Uncertain:1Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | FBN1: BS1 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 31, 2016 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 28, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 31, 2023 | See Variant Classification Assertion Criteria. - |
Familial thoracic aortic aneurysm and aortic dissection Benign:4
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 20, 2019 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 25, 2018 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 28, 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 08, 2023 | 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. - |
not specified Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 30, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Stiff skin syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 28, 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. - |
Weill-Marchesani syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 28, 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. - |
Geleophysic dysplasia Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 28, 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 | Nov 28, 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. - |
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 | Nov 28, 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Splicing
Name
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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