rs139619440
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1PP2BP4_StrongBP6BS1
The NM_000090.4(COL3A1):c.3061C>A(p.Leu1021Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,614,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. L1021V) has been classified as Likely benign.
Frequency
Consequence
NM_000090.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL3A1 | NM_000090.4 | c.3061C>A | p.Leu1021Ile | missense_variant | 42/51 | ENST00000304636.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL3A1 | ENST00000304636.9 | c.3061C>A | p.Leu1021Ile | missense_variant | 42/51 | 1 | NM_000090.4 | P1 | |
COL3A1 | ENST00000450867.2 | c.2962C>A | p.Leu988Ile | missense_variant | 41/50 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.000171 AC: 26AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000430 AC: 108AN: 251396Hom.: 0 AF XY: 0.000383 AC XY: 52AN XY: 135874
GnomAD4 exome AF: 0.000127 AC: 186AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.000120 AC XY: 87AN XY: 727236
GnomAD4 genome ? AF: 0.000177 AC: 27AN: 152328Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74484
ClinVar
Submissions by phenotype
not specified Benign:3
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 23, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 14, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 21, 2021 | Variant summary: COL3A1 c.3061C>A (p.Leu1021Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 251396 control chromosomes. The observed variant frequency is approximately 286 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL3A1 causing Ehlers-Danlos Syndrome, Vascular Type phenotype (1.5e-06), strongly suggesting that the variant is benign. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
Familial thoracic aortic aneurysm and aortic dissection Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 11, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Aug 08, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 03, 2018 | - - |
Ehlers-Danlos syndrome, type 4 Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
COL3A1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 04, 2023 | The COL3A1 c.3061C>A variant is predicted to result in the amino acid substitution p.Leu1021Ile. This variant was reported in an individual with aortic dissection, Stanford type A. However, other potentially relevant variants in other genes were also identified (Patient A180, Table 3, Chen et al. 2021. PubMed ID: 34422331). This variant is reported in 0.52% of alleles in individuals of East Asian descent in gnomAD, which is higher than expected for a highly penetrant pathogenic variant (no homozygotes have been identified, however). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at