NM_001851.6:c.*240_*242dupAAA

Variant names:

• chr6-70216654-C-CTTT
• rs3215859
• NM_001851.6:c.*240_*242dupAAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001851.6(COL9A1):​c.*240_*242dupAAA 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 0.0062 (12 hom., cov: 0)
  • Exomes 𝑓: 0.0017 (1 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):

• epiphyseal dysplasia, multiple, 6

  Inheritance: AD, AR, Unknown Classification: DEFINITIVE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Stickler syndrome, type 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00623 (909/145922) while in subpopulation AFR AF = 0.0213 (844/39656). AF 95% confidence interval is 0.0201. There are 12 homozygotes in GnomAd4. There are 453 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR,AD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A1	NM_001851.6	c.*240_*242dupAAA		3_prime_UTR_variant	Exon 38 of 38	ENST00000357250.11	NP_001842.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A1	ENST00000357250.11	c.*240_*242dupAAA		3_prime_UTR_variant	Exon 38 of 38	1	NM_001851.6	ENSP00000349790.6

Frequencies

GnomAD3 genomes AF: 0.00623 AC: 909 AN: 145880 Hom.: 12 Cov.: 0

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00305

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000201

Gnomad SAS AF: 0.000220

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000181

Gnomad OTH AF: 0.00298

GnomAD4 exome AF: 0.00169 AC: 571 AN: 336972 Hom.: 1 Cov.: 0 AF XY: 0.00166 AC XY: 294 AN XY: 177210

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

African (AFR) AF: 0.0156 AC: 149 AN: 9564

American (AMR) AF: 0.00117 AC: 17 AN: 14472

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 12 AN: 10370

East Asian (EAS) AF: 0.00 AC: 0 AN: 22322

South Asian (SAS) AF: 0.00149 AC: 56 AN: 37664

European-Finnish (FIN) AF: 0.00102 AC: 20 AN: 19676

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

European-Non Finnish (NFE) AF: 0.00139 AC: 281 AN: 202350

Other (OTH) AF: 0.00189 AC: 36 AN: 19080

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00623 AC: 909 AN: 145922 Hom.: 12 Cov.: 0 AF XY: 0.00639 AC XY: 453 AN XY: 70872

African (AFR) AF: 0.0213 AC: 844 AN: 39656

American (AMR) AF: 0.00304 AC: 45 AN: 14782

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

East Asian (EAS) AF: 0.000202 AC: 1 AN: 4958

South Asian (SAS) AF: 0.000221 AC: 1 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: 0.000181 AC: 12 AN: 66280

Other (OTH) AF: 0.00296 AC: 6 AN: 2026

Alfa AF: 0.00 Hom.: 232

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism

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;