rs760569641
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The NM_000393.5(COL5A2):c.4357C>T(p.Arg1453Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,542 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. R1453Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000393.5 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 |
---|---|---|---|---|---|---|---|
COL5A2 | NM_000393.5 | c.4357C>T | p.Arg1453Trp | missense_variant | 54/54 | ENST00000374866.9 | |
COL5A2 | XM_011510573.4 | c.4219C>T | p.Arg1407Trp | missense_variant | 57/57 | ||
COL5A2 | XM_047443251.1 | c.4219C>T | p.Arg1407Trp | missense_variant | 59/59 | ||
COL5A2 | XM_047443252.1 | c.4219C>T | p.Arg1407Trp | missense_variant | 58/58 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL5A2 | ENST00000374866.9 | c.4357C>T | p.Arg1453Trp | missense_variant | 54/54 | 1 | NM_000393.5 | P1 | |
COL5A2 | ENST00000618828.1 | c.3196C>T | p.Arg1066Trp | missense_variant | 47/47 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 151970Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250826Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135586
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461572Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727082
GnomAD4 genome AF: 0.0000197 AC: 3AN: 151970Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74204
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 15, 2019 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not located in the triple helical region, where the majority of pathogenic missense variants occur (Symoens et al., 2012; Stenson et al., 2014); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 577649; Landrum et al., 2016) - |
Ehlers-Danlos syndrome, classic type, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2018 | Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably damaging"; Align-GVGD: "Class C0"). 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. This variant has not been reported in the literature in individuals with COL5A2-related disease. This variant is present in population databases (rs760569641, ExAC 0.006%). This sequence change replaces arginine with tryptophan at codon 1453 of the COL5A2 protein (p.Arg1453Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at