chr6-70279648-CAA-C

Variant names:

• chr6-70279648-CAA-C
• rs57993118
• NM_001851.6:c.975+1162_975+1163delTT

Variant summary

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

The NM_001851.6(COL9A1):​c.975+1162_975+1163delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 58,186 control chromosomes in the GnomAD database, including 6 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.017 (6 hom., cov: 20)
  • Exomes 𝑓: 0.028 (0 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0380
• 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: 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0173 (994/57512) while in subpopulation SAS AF = 0.0508 (66/1298). AF 95% confidence interval is 0.041. There are 6 homozygotes in GnomAd4. There are 486 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD,Unknown gene

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.975+1162_975+1163delTT		intron	N/A	NP_001842.3
	COL9A1	NM_001377289.1		c.246+1162_246+1163delTT		intron	N/A	NP_001364218.1	A0A804HIB6
	COL9A1	NM_078485.4		c.246+1162_246+1163delTT		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.975+1162_975+1163delTT		intron	N/A	ENSP00000349790.6	P20849-1
	COL9A1	ENST00000320755.12	TSL:1	c.246+1162_246+1163delTT		intron	N/A	ENSP00000315252.7	P20849-2
	COL9A1	ENST00000683980.2		c.246+1162_246+1163delTT		intron	N/A	ENSP00000506990.1	A0A804HIB6

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 995 AN: 57484 Hom.: 6 Cov.: 20

Gnomad AFR AF: 0.0381

Gnomad AMI AF: 0.0505

Gnomad AMR AF: 0.00920

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0507

Gnomad FIN AF: 0.00127

Gnomad MID AF: 0.0658

Gnomad NFE AF: 0.00710

Gnomad OTH AF: 0.0169

GnomAD4 exome AF: 0.0282 AC: 19 AN: 674 Hom.: 0 AF XY: 0.0242 AC XY: 9 AN XY: 372

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

African (AFR) AF: 0.00 AC: 0 AN: 30

American (AMR) AF: 0.00 AC: 0 AN: 24

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 32

East Asian (EAS) AF: 0.0645 AC: 4 AN: 62

South Asian (SAS) AF: 0.167 AC: 1 AN: 6

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.0295 AC: 13 AN: 440

Other (OTH) AF: 0.0208 AC: 1 AN: 48

⚠️ 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: 0.0173 AC: 994 AN: 57512 Hom.: 6 Cov.: 20 AF XY: 0.0184 AC XY: 486 AN XY: 26378

African (AFR) AF: 0.0380 AC: 623 AN: 16400

American (AMR) AF: 0.00920 AC: 43 AN: 4676

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 17 AN: 1484

East Asian (EAS) AF: 0.00 AC: 0 AN: 2140

South Asian (SAS) AF: 0.0508 AC: 66 AN: 1298

European-Finnish (FIN) AF: 0.00127 AC: 2 AN: 1580

Middle Eastern (MID) AF: 0.0694 AC: 5 AN: 72

European-Non Finnish (NFE) AF: 0.00711 AC: 204 AN: 28710

Other (OTH) AF: 0.0168 AC: 12 AN: 716

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.038
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs57993118; hg19: chr6-70989351;