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rs61746008

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 Uncertain significance.

Frequency

Genomes: 𝑓 0.00071 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00076 ( 2 hom. )

Consequence

FBN1
NM_000138.5 missense

Scores

2
7
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:19

Conservation

PhyloP100: 2.13
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2
Missense variant where missense usually causes diseases, FBN1
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. This position pass quality control queck.
BS2
High AC in GnomAd at 108 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FBN1NM_000138.5 linkuse as main transcriptc.8176C>T p.Arg2726Trp missense_variant 65/66 ENST00000316623.10
FBN1NM_001406716.1 linkuse as main transcriptc.8176C>T p.Arg2726Trp missense_variant 64/65

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FBN1ENST00000316623.10 linkuse as main transcriptc.8176C>T p.Arg2726Trp missense_variant 65/661 NM_000138.5 P1

Frequencies

GnomAD3 genomes
AF:
0.000710
AC:
108
AN:
152166
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000458
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00209
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000779
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.000728
AC:
183
AN:
251466
Hom.:
1
AF XY:
0.000751
AC XY:
102
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.000492
Gnomad AMR exome
AF:
0.00173
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000888
Gnomad OTH exome
AF:
0.00147
GnomAD4 exome
AF:
0.000761
AC:
1113
AN:
1461880
Hom.:
2
Cov.:
32
AF XY:
0.000758
AC XY:
551
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.00165
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000151
Gnomad4 FIN exome
AF:
0.0000749
Gnomad4 NFE exome
AF:
0.000871
Gnomad4 OTH exome
AF:
0.000729
GnomAD4 genome
AF:
0.000709
AC:
108
AN:
152284
Hom.:
0
Cov.:
33
AF XY:
0.000658
AC XY:
49
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.000457
Gnomad4 AMR
AF:
0.00209
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000779
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000872
Hom.:
0
Bravo
AF:
0.000778
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00114
AC:
5
ESP6500EA
AF:
0.00105
AC:
9
ExAC
AF:
0.000733
AC:
89
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00109
EpiControl
AF:
0.00154

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 providedliterature onlyOMIMJan 01, 2009- -
Likely benign, criteria provided, single submitterresearchCSER _CC_NCGL, University of WashingtonDec 01, 2015- -
Likely benign, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteJun 24, 2022Based 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 submitterclinical testingMendelicsMay 28, 2019- -
Uncertain significance, no assertion criteria providedclinical testingCenter for Medical Genetics Ghent, University of GhentNov 07, 2017- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaNov 28, 2018This 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 submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityApr 19, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsSep 01, 2017This 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. -
not provided Uncertain:1Benign:3
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 28, 2021- -
Likely benign, criteria provided, single submitterclinical testingGeneDxMay 31, 2023See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 31, 2016- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2023FBN1: BS1 -
Familial thoracic aortic aneurysm and aortic dissection Benign:4
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 08, 2023This 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 submitterclinical testingColor Diagnostics, LLC DBA Color HealthApr 25, 2018- -
Likely benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioNov 20, 2019- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaNov 28, 2018This 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 specified Benign:2
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 04, 2019Variant summary: FBN1 c.8176C>T (p.Arg2726Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 252730 control chromosomes, predominantly at a frequency of 0.0017 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 16 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.8176C>T has been reported in the literature in individuals affected with Marfan Syndrome, as well as in mildly affected and unaffected family members, suggesting incomplete penetrance, or a mostly benign nature. Since the penetrance of Marfan Syndrome (0.71) due to this variant appears to be lower than expected (0.8), no conclusions can be drawn from these data. Co-occurrences with other pathogenic FBN1 variants have been reported (e.g. Stheneur 2009: c.3299G>T (p.Gly1100V), c.6388G>A (p.Glu2130Lys), c.1416C>A (p.Cys472X); Arnaud 2017: c.1585C>T (Arg529X), c.6388G>A (p.Glu2130Lys); Becerra-Munoz 2018: c.7754T>C, (p.Ile2585Thr); and in an internal sample: c.3073_3074insA (p.Phe1025fsX7)), providing supporting evidence for a benign role. Some publications also reported experimental evidence evaluating an impact on protein function, showing a decreased protein processing (C-terminal propeptide cleavage) (Milewicz 1995, Lonnqvist 1998). Ten ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (4x) and likely benign (6x). Based on the evidence outlined above, the variant was classified as likely benign. -
Stiff skin syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaNov 28, 2018This 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 submitterclinical testingIllumina Laboratory Services, IlluminaNov 28, 2018This 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 submitterclinical testingIllumina Laboratory Services, IlluminaNov 28, 2018This 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 submitterclinical testingIllumina Laboratory Services, IlluminaNov 28, 2018This 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 submitterclinical testingInvitaeJan 29, 2024- -
Ectopia lentis 1, isolated, autosomal dominant Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaNov 28, 2018This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.084
T
BayesDel_noAF
Uncertain
0.090
Cadd
Pathogenic
27
Dann
Uncertain
1.0
Eigen
Benign
-0.20
Eigen_PC
Benign
-0.13
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Benign
0.084
D
MetaRNN
Benign
0.044
T
MetaSVM
Benign
-0.35
T
MutationTaster
Benign
0.99
D
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-4.7
D
REVEL
Uncertain
0.57
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0030
D
Vest4
0.60
MVP
0.95
MPC
1.3
ClinPred
0.071
T
GERP RS
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs61746008; hg19: chr15-48704816; API