rs672601329
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PVS1_ModeratePM2BS1_Supporting
The NM_001851.6(COL9A1):c.876+2dupT variant causes a splice donor, 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
Consequence
NM_001851.6 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000313 AC: 47AN: 150346Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000211 AC: 53AN: 250708Hom.: 0 AF XY: 0.000251 AC XY: 34AN XY: 135600
GnomAD4 exome AF: 0.000308 AC: 450AN: 1460122Hom.: 0 Cov.: 31 AF XY: 0.000324 AC XY: 235AN XY: 726430
GnomAD4 genome AF: 0.000313 AC: 47AN: 150394Hom.: 0 Cov.: 31 AF XY: 0.000300 AC XY: 22AN XY: 73402
ClinVar
Submissions by phenotype
not provided Uncertain:3
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. -
COL9A1: PP3, PS3:Supporting -
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
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Epiphyseal dysplasia, multiple, 6;C3279941:Stickler syndrome, type 4 Uncertain:1
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COL9A1-related disorder Uncertain:1
The COL9A1 c.876+2dupT variant is predicted to result in an intronic duplication. This variant was reported in the heterozygous state in a patient and the mother, both affected with multiple epiphyseal dysplasia, while being absent from an unaffected sibling (described as IVS8+3, Czarny-Ratajczak et al. 2001. PubMed ID: 11565064). RNA isolated from patient lymphoblasts demonstrated this variant led to exon skipping resulting in at least three aberrant in-frame deletions (Czarny-Ratajczak et al. 2001. PubMed ID: 11565064). This variant is reported in 0.043% of alleles in individuals of European (Non-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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at