20-62821775-G-A
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3BP4_ModerateBS1_SupportingBS2
The NM_001853.4(COL9A3):c.388G>A(p.Gly130Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,610,366 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts 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. G130V) has been classified as Uncertain significance.
Frequency
Consequence
NM_001853.4 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 |
---|---|---|---|---|---|---|---|
COL9A3 | NM_001853.4 | c.388G>A | p.Gly130Ser | missense_variant | 8/32 | ENST00000649368.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL9A3 | ENST00000649368.1 | c.388G>A | p.Gly130Ser | missense_variant | 8/32 | NM_001853.4 | P1 | ||
COL9A3 | ENST00000452372.2 | c.277G>A | p.Gly93Ser | missense_variant | 7/12 | 5 | |||
COL9A3 | ENST00000477612.5 | n.384G>A | non_coding_transcript_exon_variant | 8/12 | 3 | ||||
COL9A3 | ENST00000489045.5 | n.434G>A | non_coding_transcript_exon_variant | 7/14 | 5 |
Frequencies
GnomAD3 genomes AF: 0.000907 AC: 138AN: 152160Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000829 AC: 202AN: 243632Hom.: 0 AF XY: 0.000805 AC XY: 107AN XY: 132992
GnomAD4 exome AF: 0.00110 AC: 1598AN: 1458088Hom.: 3 Cov.: 32 AF XY: 0.00105 AC XY: 763AN XY: 725242
GnomAD4 genome AF: 0.000900 AC: 137AN: 152278Hom.: 0 Cov.: 33 AF XY: 0.000819 AC XY: 61AN XY: 74462
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 03, 2023 | Reported in association with age-related macular degeneration and unspecified retinal and optical nerve disorders (Seddon et al., 2013; Dieiro et al., 2020); Reported to segregate with autosomal dominant disease in a family with bilateral vitreoretinal lattice degeneration (Nash et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32483926, 35241111, 33633367, 24036952, 36621380) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 130 of the COL9A3 protein (p.Gly130Ser). This variant is present in population databases (rs139401633, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal dominant vitreoretinal degeneration and/or blindness (PMID: 32483926, 33633367). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 392918). 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 expected to disrupt COL9A3 protein function with a positive 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2022 | COL9A3: PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 06, 2016 | - - |
Retinal detachment;C0154856:Lattice retinal degeneration Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Eye Genetics Research Group, Children's Medical Research Institute | Jul 22, 2020 | - - |
Intervertebral disc disorder;C1832998:Epiphyseal dysplasia, multiple, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 28, 2021 | - - |
Connective tissue disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jan 01, 2020 | - - |
COL9A3-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 02, 2021 | 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at