chr15-48516341-G-A
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_000138.5(FBN1):c.1169C>T(p.Ser390Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000632 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict 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. S390P) has been classified as Uncertain significance.
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.1169C>T | p.Ser390Phe | missense_variant | 11/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.1169C>T | p.Ser390Phe | missense_variant | 10/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.1169C>T | p.Ser390Phe | missense_variant | 11/66 | 1 | NM_000138.5 | P1 | |
FBN1 | ENST00000559133.6 | c.1169C>T | p.Ser390Phe | missense_variant, NMD_transcript_variant | 11/67 | 1 | |||
FBN1 | ENST00000674301.2 | c.1169C>T | p.Ser390Phe | missense_variant, NMD_transcript_variant | 11/68 | ||||
FBN1 | ENST00000537463.6 | c.636+21370C>T | intron_variant, NMD_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000240 AC: 6AN: 250224Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135392
GnomAD4 exome AF: 0.0000684 AC: 100AN: 1461534Hom.: 0 Cov.: 33 AF XY: 0.0000688 AC XY: 50AN XY: 727084
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74342
ClinVar
Submissions by phenotype
Marfan syndrome Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Center for Medical Genetics Ghent, University of Ghent | Nov 07, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 30, 2023 | This missense variant replaces serine with phenylalanine at codon 390 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/250224 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 25, 2019 | The FBN1 c.1169C>T; p.Ser390Phe variant (rs746385384) is reported in the medical literature in an individual with craniosynostosis, but the variant was not determined to be causative (Clarke 2018). The variant is listed in the ClinVar database (Variation ID: 549007) and in the general population in 6 out of 244982 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at this position is weakly conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is tolerated. Considering available information, the clinical significance of this variant is uncertain at this time. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 18, 2023 | This missense variant replaces serine with phenylalanine at codon 390 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with FBN1-related disorders in the literature. This variant has been identified in 6/250224 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The FBN1 p.Ser390Phe variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs746385384) and ClinVar (classified as a VUS by Invitae and Center for Medical Genetics Ghent, University of Ghent for Marfan Syndrome and Thoracic aortic aneurysm and aortic dissection). The variant was identified in control databases in 6 of 250224 chromosomes at a frequency of 0.000024 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (non-Finnish) population in 6 of 112904 chromosomes (freq: 0.000053), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The p.Ser390 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jun 14, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at