chr9-134699972-C-A
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4BP6_Very_StrongBS2
The NM_000093.5(COL5A1):c.341C>A(p.Ala114Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000858 in 1,613,828 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A114G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000093.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL5A1 | NM_000093.5 | c.341C>A | p.Ala114Asp | missense_variant | 3/66 | ENST00000371817.8 | |
COL5A1 | NM_001278074.1 | c.341C>A | p.Ala114Asp | missense_variant | 3/66 | ||
COL5A1 | XM_017014266.3 | c.341C>A | p.Ala114Asp | missense_variant | 3/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL5A1 | ENST00000371817.8 | c.341C>A | p.Ala114Asp | missense_variant | 3/66 | 1 | NM_000093.5 | P4 | |
COL5A1 | ENST00000371820.4 | c.341C>A | p.Ala114Asp | missense_variant | 3/66 | 2 | A2 | ||
COL5A1 | ENST00000464187.1 | n.763C>A | non_coding_transcript_exon_variant | 4/6 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000709 AC: 108AN: 152232Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000585 AC: 147AN: 251324Hom.: 0 AF XY: 0.000581 AC XY: 79AN XY: 135876
GnomAD4 exome AF: 0.000874 AC: 1277AN: 1461596Hom.: 0 Cov.: 32 AF XY: 0.000838 AC XY: 609AN XY: 727074
GnomAD4 genome AF: 0.000709 AC: 108AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.000659 AC XY: 49AN XY: 74376
ClinVar
Submissions by phenotype
not provided Benign:4
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 26, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 07, 2020 | This variant is associated with the following publications: (PMID: 29924831, 28550590, 15580559) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | COL5A1: BS1 - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
not specified Benign:2
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 07, 2023 | Variant summary: COL5A1 c.341C>A (p.Ala114Asp) results in a non-conservative amino acid change located in the Lamnin G domain (IPR001791) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 251324 control chromosomes (gnomAD). The observed variant frequency is approximately 19 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL5A1 causing Ehlers-Danlos Syndrome phenotype (3.1e-05), strongly suggesting that the variant is benign. c.341C>A has been reported in the literature in individuals affected with keratoconus and hereditary palmoplantar keratodermas (examples: Lucas_2018, Harjama_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Ehlers-Danlos Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33914963, 29924831). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
COL5A1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 04, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 19, 2019 | 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. - |
Ehlers-Danlos syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Nov 24, 2021 | - - |
Ehlers-Danlos syndrome, classic type Benign:1
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Ehlers-Danlos syndrome, classic type, 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Connective tissue disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Jun 01, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at