rs147157552
Positions:
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2
The NM_001999.4(FBN2):c.518C>T(p.Thr173Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00128 in 1,608,094 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0013 ( 3 hom. )
Consequence
FBN2
NM_001999.4 missense
NM_001999.4 missense
Scores
7
11
Clinical Significance
Conservation
PhyloP100: 4.49
Genes affected
FBN2 (HGNC:3604): (fibrillin 2) The protein encoded by this gene is a component of connective tissue microfibrils and may be involved in elastic fiber assembly. Mutations in this gene cause congenital contractural arachnodactyly. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -10 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001999.4
PP2
?
Missense variant where missense usually causes diseases, FBN2
BP4
?
Computational evidence support a benign effect (MetaRNN=0.017662913).
BP6
?
Variant 5-128527886-G-A is Benign according to our data. Variant chr5-128527886-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 155796.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=10, Uncertain_significance=2}. Variant chr5-128527886-G-A is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00108 (165/152250) while in subpopulation NFE AF= 0.00194 (132/68008). AF 95% confidence interval is 0.00167. There are 0 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 165 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN2 | NM_001999.4 | c.518C>T | p.Thr173Ile | missense_variant | 4/65 | ENST00000262464.9 | |
FBN2 | XM_017009228.3 | c.518C>T | p.Thr173Ile | missense_variant | 4/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.518C>T | p.Thr173Ile | missense_variant | 4/65 | 1 | NM_001999.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00108 AC: 165AN: 152132Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00116 AC: 292AN: 250682Hom.: 0 AF XY: 0.00125 AC XY: 169AN XY: 135494
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GnomAD4 exome AF: 0.00130 AC: 1898AN: 1455844Hom.: 3 Cov.: 29 AF XY: 0.00134 AC XY: 969AN XY: 724632
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GnomAD4 genome ? AF: 0.00108 AC: 165AN: 152250Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84AN XY: 74448
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:13
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:5
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 27, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 16, 2021 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | FBN2: BS1 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 12, 2014 | - - |
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 30, 2015 | Variant classified as Uncertain Significance - Favor Benign. The p.Thr173Ile var iant in FBN2 has not been previously reported in individuals with connective tis sue disorders. It has been identified in 0.2% (146/65724) of European chromosom es, including 1 homozygous individual, by the Exome Aggregation Consortium (ExAC , http://exac.broadinstitute.org; dbSNP rs147157552). Computational prediction t ools and conservation analysis suggest that this variant may not impact the prot ein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Thr173Ile variant is uncer tain, its frequency and lack of conservation suggests that it is more likely to be benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 06, 2023 | - - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 29, 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Blueprint Genetics | May 19, 2014 | - - |
Congenital contractural arachnodactyly Benign:2
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | - - |
Connective tissue disorder Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jun 20, 2022 | - - |
FBN2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 01, 2019 | 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). - |
Ehlers-Danlos syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 01, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.;D;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;.;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;L;.;.
MutationTaster
Benign
N;N;N;N
PrimateAI
Benign
T
PROVEAN
Uncertain
D;.;D;D;D
REVEL
Uncertain
Sift
Benign
D;.;D;D;T
Polyphen
B;.;B;B;B
Vest4
MVP
MPC
0.53
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Score
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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