rs534898281
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBS1_Supporting
The NM_000090.4(COL3A1):c.272C>T(p.Pro91Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000090.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL3A1 | ENST00000304636.9 | c.272C>T | p.Pro91Leu | missense_variant | Exon 2 of 51 | 1 | NM_000090.4 | ENSP00000304408.4 | ||
COL3A1 | ENST00000450867.2 | c.272C>T | p.Pro91Leu | missense_variant | Exon 2 of 50 | 1 | ENSP00000415346.2 | |||
COL3A1 | ENST00000470167.1 | n.368C>T | non_coding_transcript_exon_variant | Exon 2 of 2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000461 AC: 7AN: 151952Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460664Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726670
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152070Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74334
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:2
The p.P91L variant (also known as c.272C>T), located in coding exon 2 of the COL3A1 gene, results from a C to T substitution at nucleotide position 272. The proline at codon 91 is replaced by leucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
This missense variant replaces proline with leucine at codon 91 of the COL3A1 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 reported for this variant. This variant has not been reported in individuals affected with COL3A1-related disorders in the literature. This variant has been identified in 1/31382 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. -
Ehlers-Danlos syndrome, type 4 Uncertain:2
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 91 of the COL3A1 protein (p.Pro91Leu). This variant is present in population databases (rs534898281, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 529312). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt COL3A1 protein function with a negative predictive value of 95%. 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 missense variant replaces proline with leucine at codon 91 of the COL3A1 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 reported for this variant. This variant has not been reported in individuals affected with COL3A1-related disorders in the literature. This variant has been identified in 1/31382 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. -
Ehlers-Danlos syndrome, type 4;C5193040:Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome Uncertain:1
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not provided Uncertain:1
Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at