rs201375465
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2PP3_ModerateBS2
The NM_000093.5(COL5A1):c.1388C>T(p.Pro463Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000167 in 1,614,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. P463S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000093.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL5A1 | NM_000093.5 | c.1388C>T | p.Pro463Leu | missense_variant, splice_region_variant | 9/66 | ENST00000371817.8 | |
COL5A1 | NM_001278074.1 | c.1388C>T | p.Pro463Leu | missense_variant, splice_region_variant | 9/66 | ||
COL5A1 | XM_017014266.3 | c.1388C>T | p.Pro463Leu | missense_variant, splice_region_variant | 9/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL5A1 | ENST00000371817.8 | c.1388C>T | p.Pro463Leu | missense_variant, splice_region_variant | 9/66 | 1 | NM_000093.5 | P4 | |
COL5A1 | ENST00000371820.4 | c.1388C>T | p.Pro463Leu | missense_variant, splice_region_variant | 9/66 | 2 | A2 | ||
COL5A1 | ENST00000469093.1 | n.127C>T | non_coding_transcript_exon_variant | 2/2 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152240Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251492Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135920
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461862Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 727234
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152358Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74512
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (PMID: 22696272; HGMD); This variant is associated with the following publications: (PMID: 22696272, 34422331) - |
Ehlers-Danlos syndrome, classic type, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 30, 2021 | This sequence change replaces proline with leucine at codon 463 of the COL5A1 protein (p.Pro463Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs201375465, ExAC 0.02%). This variant has not been reported in the literature in individuals affected with COL5A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 213025). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at