6-70216654-CTTTT-CTTTTTTTT

Variant names:

• chr6-70216654-C-CTTTT
• rs3215859
• NM_001851.6:c.*239_*242dupAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001851.6(COL9A1):​c.*239_*242dupAAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000096 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: COL9A1 NM_001851.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.00
• Publications: 2 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: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• epiphyseal dysplasia, multiple, 6

  Inheritance: Unknown, AD, AR Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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 0 ACMG points.

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.*239_*242dupAAAA		3_prime_UTR	Exon 38 of 38	NP_001842.3
	COL9A1	NM_001377289.1		c.*239_*242dupAAAA		3_prime_UTR	Exon 33 of 33	NP_001364218.1	A0A804HIB6
	COL9A1	NM_078485.4		c.*239_*242dupAAAA		3_prime_UTR	Exon 32 of 32	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.*239_*242dupAAAA		3_prime_UTR	Exon 38 of 38	ENSP00000349790.6	P20849-1
	COL9A1	ENST00000320755.12	TSL:1	c.*239_*242dupAAAA		3_prime_UTR	Exon 32 of 32	ENSP00000315252.7	P20849-2
	COL9A1	ENST00000683980.2		c.*239_*242dupAAAA		3_prime_UTR	Exon 33 of 33	ENSP00000506990.1	A0A804HIB6

Frequencies

GnomAD3 genomes AF: 0.0000960 AC: 14 AN: 145884 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000677

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000771 AC: 26 AN: 337244 Hom.: 0 Cov.: 0 AF XY: 0.0000846 AC XY: 15 AN XY: 177346

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000938 AC: 9 AN: 9590

American (AMR) AF: 0.0000690 AC: 1 AN: 14488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10376

East Asian (EAS) AF: 0.00 AC: 0 AN: 22340

South Asian (SAS) AF: 0.0000531 AC: 2 AN: 37694

European-Finnish (FIN) AF: 0.000102 AC: 2 AN: 19690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1474

European-Non Finnish (NFE) AF: 0.0000494 AC: 10 AN: 202502

Other (OTH) AF: 0.000105 AC: 2 AN: 19090

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000959 AC: 14 AN: 145926 Hom.: 0 Cov.: 0 AF XY: 0.0000847 AC XY: 6 AN XY: 70874

African (AFR) AF: 0.000328 AC: 13 AN: 39660

American (AMR) AF: 0.0000676 AC: 1 AN: 14782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3408

East Asian (EAS) AF: 0.00 AC: 0 AN: 4958

South Asian (SAS) AF: 0.00 AC: 0 AN: 4528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66280

Other (OTH) AF: 0.00 AC: 0 AN: 2026

Alfa AF: 0.00 Hom.: 232

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.0

Splicing

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

Other links and lift over

dbSNP: rs3215859; hg19: chr6-70926357;