chr9-134701276-C-G
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_ModerateBP6_Very_StrongBS2
The NM_000093.5(COL5A1):c.597C>G(p.Ile199Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000271 in 1,614,002 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I199V) has been classified as Benign.
Frequency
Consequence
NM_000093.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL5A1 | NM_000093.5 | c.597C>G | p.Ile199Met | missense_variant | 4/66 | ENST00000371817.8 | |
COL5A1 | NM_001278074.1 | c.597C>G | p.Ile199Met | missense_variant | 4/66 | ||
COL5A1 | XM_017014266.3 | c.597C>G | p.Ile199Met | missense_variant | 4/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL5A1 | ENST00000371817.8 | c.597C>G | p.Ile199Met | missense_variant | 4/66 | 1 | NM_000093.5 | P4 | |
COL5A1 | ENST00000371820.4 | c.597C>G | p.Ile199Met | missense_variant | 4/66 | 2 | A2 | ||
COL5A1 | ENST00000464187.1 | n.1019C>G | non_coding_transcript_exon_variant | 5/6 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000742 AC: 113AN: 152230Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000352 AC: 88AN: 250316Hom.: 0 AF XY: 0.000332 AC XY: 45AN XY: 135682
GnomAD4 exome AF: 0.000222 AC: 325AN: 1461654Hom.: 2 Cov.: 33 AF XY: 0.000230 AC XY: 167AN XY: 727116
GnomAD4 genome ? AF: 0.000742 AC: 113AN: 152348Hom.: 0 Cov.: 33 AF XY: 0.000752 AC XY: 56AN XY: 74492
ClinVar
Submissions by phenotype
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 06, 2024 | Variant summary: COL5A1 c.597C>G (p.Ile199Met) results in a conservative amino acid change located in the Laminin G domain (IPR001791) of 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 0.00035 in 250316 control chromosomes. The observed variant frequency is approximately 11.25 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.597C>G has been reported in the literature in individuals affected with Ehlers-Danlos Syndrome. 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. ClinVar contains an entry for this variant (Variation ID: 213070). 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 | Dec 11, 2023 | 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 | Nov 05, 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. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 28, 2020 | This variant is associated with the following publications: (PMID: 28454995, 29924831) - |
Ehlers-Danlos syndrome, classic type Benign:1
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 13, 2018 | - - |
Ehlers-Danlos syndrome, classic type, 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 23, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at