rs672601329
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP3_ModerateBS1_Supporting
The NM_001851.6(COL9A1):c.876+2_876+3insT variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000309 in 1,610,516 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00031 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00031 ( 0 hom. )
Consequence
COL9A1
NM_001851.6 splice_region, intron
NM_001851.6 splice_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.21
Genes affected
COL9A1 (HGNC:2217): (collagen type IX alpha 1 chain) This gene encodes one of the three alpha chains of type IX collagen, which is a minor (5-20%) collagen component of hyaline cartilage. Type IX collagen is usually found in tissues containing type II collagen, a fibrillar collagen. Studies in knockout mice have shown that synthesis of the alpha 1 chain is essential for assembly of type IX collagen molecules, a heterotrimeric molecule, and that lack of type IX collagen is associated with early onset osteoarthritis. Mutations in this gene are associated with osteoarthritis in humans, with multiple epiphyseal dysplasia, 6, a form of chondrodysplasia, and with Stickler syndrome, a disease characterized by ophthalmic, orofacial, articular, and auditory defects. Two transcript variants that encode different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000313 (47/150394) while in subpopulation NFE AF= 0.000636 (43/67624). AF 95% confidence interval is 0.000484. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL9A1 | NM_001851.6 | c.876+2_876+3insT | splice_region_variant, intron_variant | ENST00000357250.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL9A1 | ENST00000357250.11 | c.876+2_876+3insT | splice_region_variant, intron_variant | 1 | NM_001851.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000313 AC: 47AN: 150346Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000211 AC: 53AN: 250708Hom.: 0 AF XY: 0.000251 AC XY: 34AN XY: 135600
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GnomAD4 exome AF: 0.000308 AC: 450AN: 1460122Hom.: 0 Cov.: 31 AF XY: 0.000324 AC XY: 235AN XY: 726430
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GnomAD4 genome ? AF: 0.000313 AC: 47AN: 150394Hom.: 0 Cov.: 31 AF XY: 0.000300 AC XY: 22AN XY: 73402
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | This sequence change falls in intron 8 of the COL9A1 gene. It does not directly change the encoded amino acid sequence of the COL9A1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs672601329, gnomAD 0.04%). This variant has been observed in individual(s) with multiple epiphyseal dysplasia (PMID: 11565064). ClinVar contains an entry for this variant (Variation ID: 17194). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exons 8 and/or 10, but is expected to preserve the integrity of the reading-frame (PMID: 11565064). 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 | Dec 01, 2022 | COL9A1: PP3, PS3:Supporting - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 06, 2024 | Reported in a patient with multiple epiphyseal dysplasia and his affected mother (PMID: 11565064); Canonical splice site variant with an unclear effect on protein function; Published functional studies demonstrate abnormal gene splicing that results in in-frame deletion of 25, 21, or 46 amino acid codons; however, it is not known whether there is production of a stable abnormal protein or, if so, how protein function would be affected (PMID: 11565064); This variant is associated with the following publications: (PMID: 11565064) - |
Epiphyseal dysplasia, multiple, 6 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2001 | - - |
Epiphyseal dysplasia, multiple, 6;C3279941:Stickler syndrome, type 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 08, 2022 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at