rs672601329
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]
Genome browser will be placed here
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. 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
GnomAD3 genomes
?
AF:
AC:
47
AN:
150346
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000211 AC: 53AN: 250708Hom.: 0 AF XY: 0.000251 AC XY: 34AN XY: 135600
GnomAD3 exomes
AF:
AC:
53
AN:
250708
Hom.:
AF XY:
AC XY:
34
AN XY:
135600
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000308 AC: 450AN: 1460122Hom.: 0 Cov.: 31 AF XY: 0.000324 AC XY: 235AN XY: 726430
GnomAD4 exome
AF:
AC:
450
AN:
1460122
Hom.:
Cov.:
31
AF XY:
AC XY:
235
AN XY:
726430
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.000313 AC: 47AN: 150394Hom.: 0 Cov.: 31 AF XY: 0.000300 AC XY: 22AN XY: 73402
GnomAD4 genome
?
AF:
AC:
47
AN:
150394
Hom.:
Cov.:
31
AF XY:
AC XY:
22
AN XY:
73402
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
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 | 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. - |
Epiphyseal dysplasia, multiple, 6 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2001 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 02, 2017 | A variant of uncertain significance has been identified in the COL9A1 gene. The c.876+2dupT variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). The c.876+2duptT variant is predicted to destroy the canonical splice donor site in intron 8 with the adjacent exon remaining inframe. This variant may result in abnormal gene splicing; however, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. - |
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
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
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