rs672601329

Positions:

• chr6-70281387-T-TA

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP3_Moderate BS1_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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:5
• 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]

ACMG classification

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	Protein	UniProt
COL9A1	NM_001851.6	c.876+2_876+3insT		splice_region_variant, intron_variant		ENST00000357250.11	NP_001842.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL9A1	ENST00000357250.11	c.876+2_876+3insT		splice_region_variant, intron_variant		1	NM_001851.6	ENSP00000349790	P1

Frequencies

GnomAD3 genomes AF: 0.000313 AC: 47 AN: 150346 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000736

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000636

Gnomad OTH AF: 0.000485

GnomAD3 exomes AF: 0.000211 AC: 53 AN: 250708 Hom.: 0 AF XY: 0.000251 AC XY: 34 AN XY: 135600

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000406

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000308 AC: 450 AN: 1460122 Hom.: 0 Cov.: 31 AF XY: 0.000324 AC XY: 235 AN XY: 726430

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000376

Gnomad4 OTH exome AF: 0.000332

GnomAD4 genome AF: 0.000313 AC: 47 AN: 150394 Hom.: 0 Cov.: 31 AF XY: 0.000300 AC XY: 22 AN XY: 73402

Gnomad4 AFR AF: 0.0000735

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000636

Gnomad4 OTH AF: 0.000480

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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

- -

COL9A1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2024

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: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs672601329; hg19: chr6-70991090;