20-62817090-C-CGCTCCT
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4
The NM_001853.4(COL9A3):c.43_48dup(p.Leu15_Leu16dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,394,654 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P9P) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000053 ( 0 hom. )
Consequence
COL9A3
NM_001853.4 inframe_insertion
NM_001853.4 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.107
Genes affected
COL9A3 (HGNC:2219): (collagen type IX alpha 3 chain) This gene encodes one of the three alpha chains of type IX collagen, the major collagen component of hyaline cartilage. Type IX collagen, a heterotrimeric molecule, is usually found in tissues containing type II collagen, a fibrillar collagen. Mutations in this gene are associated with multiple epiphyseal dysplasia type 3. [provided by RefSeq, Jan 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_001853.4.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| COL9A3 | NM_001853.4 | c.43_48dup | p.Leu15_Leu16dup | inframe_insertion | 1/32 | ENST00000649368.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| COL9A3 | ENST00000649368.1 | c.43_48dup | p.Leu15_Leu16dup | inframe_insertion | 1/32 | NM_001853.4 | P1 | ||
| COL9A3 | ENST00000477612.5 | n.75-460_75-455dup | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes 0.0000264 AC: 4AN: 151322Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000123 AC: 1AN: 81068Hom.: 0 AF XY: 0.0000213 AC XY: 1AN XY: 46948
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GnomAD4 exome AF: 0.0000531 AC: 66AN: 1243332Hom.: 0 Cov.: 30 AF XY: 0.0000522 AC XY: 32AN XY: 613174
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GnomAD4 genome 0.0000264 AC: 4AN: 151322Hom.: 0 Cov.: 33 AF XY: 0.0000406 AC XY: 3AN XY: 73880
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 06, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In-frame insertion of 2 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 27, 2023 | This variant, c.43_48dup, results in the insertion of 2 amino acid(s) of the COL9A3 protein (p.Leu15_Leu16dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with COL9A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1422320). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
COL9A3-related disorder Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 22, 2024 | The COL9A3 c.43_48dup6 variant is predicted to result in an in-frame duplication (p.Leu15_Leu16dup). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.013% of alleles in individuals of European (Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at