5-128312750-T-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PP2PP3_ModerateBP6BS2
The NM_001999.4(FBN2):c.4763A>T(p.Asp1588Val) variant causes a missense change. The variant allele was found at a frequency of 0.000131 in 1,613,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D1588Y) has been classified as Uncertain significance.
Frequency
Consequence
NM_001999.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN2 | NM_001999.4 | c.4763A>T | p.Asp1588Val | missense_variant | 37/65 | ENST00000262464.9 | |
FBN2 | XM_017009228.3 | c.4610A>T | p.Asp1537Val | missense_variant | 36/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.4763A>T | p.Asp1588Val | missense_variant | 37/65 | 1 | NM_001999.4 | P1 | |
FBN2 | ENST00000703783.1 | n.1547A>T | non_coding_transcript_exon_variant | 12/38 | |||||
FBN2 | ENST00000703785.1 | n.1583-797A>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0000792 AC: 12AN: 151528Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000996 AC: 25AN: 251048Hom.: 0 AF XY: 0.0000958 AC XY: 13AN XY: 135680
GnomAD4 exome AF: 0.000136 AC: 199AN: 1461722Hom.: 0 Cov.: 32 AF XY: 0.000132 AC XY: 96AN XY: 727172
GnomAD4 genome AF: 0.0000792 AC: 12AN: 151528Hom.: 0 Cov.: 32 AF XY: 0.0000405 AC XY: 3AN XY: 73984
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 11, 2024 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 04, 2021 | - - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 11, 2023 | The p.D1588V variant (also known as c.4763A>T), located in coding exon 37 of the FBN2 gene, results from an A to T substitution at nucleotide position 4763. The aspartic acid at codon 1588 is replaced by valine, an amino acid with highly dissimilar properties. This variant was previously reported in the SNPDatabase as rs202218356. Based on data from ExAC, the T allele has an overall frequency less than 0.01% (6/106189). This variant was not reported in population based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
FBN2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 29, 2024 | 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). - |
Congenital contractural arachnodactyly Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at