chr15-48489890-C-T
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1PP2BP6BS1
The NM_000138.5(FBN1):c.3043G>A(p.Ala1015Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,614,164 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
Publications
- familial thoracic aortic aneurysm and aortic dissectionInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- Marfan syndromeInheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P, PanelApp Australia, Orphanet, Ambry Genetics
- Acromicric dysplasiaInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
- progeroid and marfanoid aspect-lipodystrophy syndromeInheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
- stiff skin syndromeInheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- Weill-Marchesani syndrome 2, dominantInheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
- geleophysic dysplasiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- isolated ectopia lentisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- neonatal Marfan syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Weill-Marchesani syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- ectopia lentis 1, isolated, autosomal dominantInheritance: AD Classification: LIMITED Submitted by: G2P
- Shprintzen-Goldberg syndromeInheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152158Hom.: 0 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.0000199 AC: 5AN: 251396 AF XY: 0.00000736 show subpopulations
GnomAD4 exome AF: 0.0000568 AC: 83AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 38AN XY: 727248 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152276Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74472 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Marfan syndrome Uncertain:3
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The NM_000138.5:c.3043G>A is considered to be not rare in the general population database (gnomAD v2.1.1). In summary, the available evidence is currently insufficient to evaluate the pathogenicity of this variant, resulting its classification as a variant of uncertain significance (BS1). -
This missense variant replaces alanine with threonine at codon 1015 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 performed for this variant. This variant has been reported in two Japanese individuals affected with Marfan syndrome (PMID: 16835936, 21907952). One of these individuals carried a pathogenic variant in the same gene. This variant has been identified in 5/251396 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. -
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1Benign:1
This missense variant replaces alanine with threonine at codon 1015 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 performed for this variant. This variant has been reported in two individuals affected with or suspected of having Marfan syndrome (PMID: 16835936, 21907952). This variant has been identified in 5/251396 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. -
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 provided Uncertain:1
Has been reported in patients with Marfan syndrome or craniosynostosis (PMID: 16835936, 21907952, 31754721); Not observed at significant frequency in large population cohorts (gnomAD); Does not affect a cysteine or calcium-binding residue within an EGF-like domain or a TGF-binding protein domain of the FBN1 gene; cysteine substitutions in the EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26332594, 31754721, 16835936, 21907952, 31227806, 12938084) -
not specified Benign:1
Variant summary: FBN1 c.3043G>A (p.Ala1015Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251396 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. However, the variant was reported in some East Asian subpopulations with a much higher allele frequency, e.g. in the Japanese, with an allele frequency of 0.0041 (in the jMorp database). This frequency is about 37-fold higher than the estimated maximum expected for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), suggesting the variant could be a benign polymorphism. c.3043G>A has been reported in the literature in individuals affected with (suspected) Marfan Syndrome (Sakai_2006, Ogawa_2011), however, in one of these cases a co-occurring possibly pathogenic variant could explain the phenotype. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A recent study combining ACMG criteria with FBN1 gene-specific knowledge (i.e. considering critical FBN1 regions and appropriate minor allele frequency (MAF) cutoffs), classified the variant as likely benign (Baudhuin_2019). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at