rs672601329

Variant names:

• chr6-70281387-T-TA
• rs672601329
• NM_001851.6:c.876+2dupT

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PVS1_Moderate BS1_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:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: COL9A1 NM_001851.6 splice_donor, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:6
• Conservation: PhyloP100: 6.21
• Publications: 0 publications found

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]

COL9A1 Gene-Disease associations (from GenCC):

• Stickler syndrome, type 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, ClinGen, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• epiphyseal dysplasia, multiple, 6

  Inheritance: Unknown, AR, AD Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• multiple epiphyseal dysplasia due to collagen 9 anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Stickler syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Stickler syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.027114967 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001851.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A1	NM_001851.6	MANE Select	c.876+2dupT		splice_donor intron	N/A	NP_001842.3
	COL9A1	NM_001377289.1		c.147+2dupT		splice_donor intron	N/A	NP_001364218.1	A0A804HIB6
	COL9A1	NM_078485.4		c.147+2dupT		splice_donor intron	N/A	NP_511040.2	P20849-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A1	ENST00000357250.11	TSL:1 MANE Select	c.876+2_876+3insT		splice_donor intron	N/A	ENSP00000349790.6	P20849-1
	COL9A1	ENST00000320755.12	TSL:1	c.147+2_147+3insT		splice_donor intron	N/A	ENSP00000315252.7	P20849-2
	COL9A1	ENST00000370496.3	TSL:1	c.876+2_876+3insT		splice_donor intron	N/A	ENSP00000359527.3	P20849-3

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

GnomAD2 exomes AF: 0.000211 AC: 53 AN: 250708 AF XY: 0.000251

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.000376 AC: 418 AN: 1110836

Other (OTH) AF: 0.000332 AC: 20 AN: 60266

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

African (AFR) AF: 0.0000735 AC: 3 AN: 40824

American (AMR) AF: 0.00 AC: 0 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 4978

South Asian (SAS) AF: 0.00 AC: 0 AN: 4736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.000636 AC: 43 AN: 67624

Other (OTH) AF: 0.000480 AC: 1 AN: 2082

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	2	-	Epiphyseal dysplasia, multiple, 6;C3279941:Stickler syndrome, type 4 (2)
-	1	-	COL9A1-related disorder (1)
1	-	-	Epiphyseal dysplasia, multiple, 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.2
Mutation Taster		=9/91	disease causing

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

Other links and lift over

dbSNP: rs672601329; hg19: chr6-70991090;