rs372269408
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate
The NM_000090.4(COL3A1):c.198A>G(p.Ile66Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000824 in 1,613,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign 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. I66L) has been classified 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 -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL3A1 | NM_000090.4 | c.198A>G | p.Ile66Met | missense_variant | 2/51 | ENST00000304636.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL3A1 | ENST00000304636.9 | c.198A>G | p.Ile66Met | missense_variant | 2/51 | 1 | NM_000090.4 | P1 | |
COL3A1 | ENST00000450867.2 | c.198A>G | p.Ile66Met | missense_variant | 2/50 | 1 | |||
COL3A1 | ENST00000470167.1 | n.294A>G | non_coding_transcript_exon_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151962Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250798Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135514
GnomAD4 exome AF: 0.0000903 AC: 132AN: 1461176Hom.: 0 Cov.: 31 AF XY: 0.0000757 AC XY: 55AN XY: 726912
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151962Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74220
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 09, 2020 | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27011056, 23148498) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 19, 2022 | BP4, PP2 - |
Ehlers-Danlos syndrome, type 4 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 02, 2023 | This missense variant replaces isoleucine with methionine at codon 66 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 been reported in one individual affected with Ehlers-Danlos syndrome hypermobility type or benign joint hypermobility syndrome (PMID: 27011056). This variant has been identified in 7/250798 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 02, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 66 of the COL3A1 protein (p.Ile66Met). This variant is present in population databases (rs372269408, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of Ehlers-Danlos syndrome (PMID: 27011056). ClinVar contains an entry for this variant (Variation ID: 263619). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 09, 2023 | This missense variant replaces isoleucine with methionine at codon 66 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 been reported in one individual affected with Ehlers-Danlos syndrome hypermobility type or benign joint hypermobility syndrome (PMID: 27011056). This variant has been identified in 7/250798 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. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 06, 2015 | Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign);Rarity in general population databases (dbsnp, esp, 1000 genomes) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at