rs761543775
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2PP3
The NM_000393.5(COL5A2):c.3268C>T(p.Pro1090Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,968 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1090T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000393.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL5A2 | NM_000393.5 | c.3268C>T | p.Pro1090Ser | missense_variant | 46/54 | ENST00000374866.9 | |
COL5A2 | XM_011510573.4 | c.3130C>T | p.Pro1044Ser | missense_variant | 49/57 | ||
COL5A2 | XM_047443251.1 | c.3130C>T | p.Pro1044Ser | missense_variant | 51/59 | ||
COL5A2 | XM_047443252.1 | c.3130C>T | p.Pro1044Ser | missense_variant | 50/58 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL5A2 | ENST00000374866.9 | c.3268C>T | p.Pro1090Ser | missense_variant | 46/54 | 1 | NM_000393.5 | P1 | |
COL5A2 | ENST00000618828.1 | c.2107C>T | p.Pro703Ser | missense_variant | 39/47 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251376Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135850
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461834Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5AN XY: 727222
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74316
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jan 20, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 18, 2016 | TAAD is a genetically heterogeneous disorder characterized by aortic dilatation, aneurysms, dissections and/or aneurysms of other major arteries. Approximately 4% of patients with autosomal dominant Ehlers-Danlos syndrome, classic type, have been reported to have a mutation in the COL5A2 gene (Malfait F et al., 2011). p.Pro1090Ser (CCT>TCT): c.3268 C>T in exon 46 of the COL5A2 gene (NM_000393.3)The Pro1090Ser variant in the COL5A2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The Pro1090Ser variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Pro1090Ser results in a non-conservative amino acid substitution of a non-polar, sterically constrained Proline with a polar Serine at a position in the triple helix region that is well conserved across species. Consequently, in silico analysis predicts Pro1090Ser is damaging to the protein structure/function. However, mutations in nearby residues have not been reported, and missense mutations in the triple helix region almost invariable involve substitution of a Glycine residue (Malfait F et al., 2011).With the clinical and molecular information available at this time, we cannot definitively determine if Pro1090Ser is a disease-causing mutation or a rare benign variant. This variant was found in TAAD. - |
Ehlers-Danlos syndrome, classic type, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 05, 2021 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with COL5A2-related conditions. This variant is present in population databases (rs761543775, ExAC 0.01%). This sequence change replaces proline with serine at codon 1090 of the COL5A2 protein (p.Pro1090Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at