6-70302872-T-C

Variant names:

• chr6-70302872-T-C
• rs2242588
• NM_001851.6:c.14+39A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001851.6(COL9A1):​c.14+39A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 1,608,776 control chromosomes in the GnomAD database, including 28,868 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4054 hom., cov: 31)
  • Exomes 𝑓: 0.18 (24814 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0840
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-70302872-T-C is Benign according to our data. Variant chr6-70302872-T-C is described in ClinVar as Benign. ClinVar VariationId is 258342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A1	NM_001851.6	MANE Select	c.14+39A>G		intron	N/A	NP_001842.3
	COL9A1	NM_001377291.1		c.14+39A>G		intron	N/A	NP_001364220.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A1	ENST00000357250.11	TSL:1 MANE Select	c.14+39A>G		intron	N/A	ENSP00000349790.6
	COL9A1	ENST00000370496.3	TSL:1	c.14+39A>G		intron	N/A	ENSP00000359527.3

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32756 AN: 151764 Hom.: 4033 Cov.: 31

Gnomad AFR AF: 0.330

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.191

GnomAD2 exomes AF: 0.186 AC: 46808 AN: 251414 AF XY: 0.184

Gnomad AFR exome AF: 0.341

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.172

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.175

Gnomad OTH exome AF: 0.168

GnomAD4 exome AF: 0.181 AC: 263509 AN: 1456894 Hom.: 24814 Cov.: 30 AF XY: 0.182 AC XY: 132174 AN XY: 725052

African (AFR) AF: 0.348 AC: 11595 AN: 33330

American (AMR) AF: 0.173 AC: 7755 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3955 AN: 26116

East Asian (EAS) AF: 0.192 AC: 7605 AN: 39682

South Asian (SAS) AF: 0.229 AC: 19694 AN: 86142

European-Finnish (FIN) AF: 0.127 AC: 6795 AN: 53420

Middle Eastern (MID) AF: 0.149 AC: 856 AN: 5762

European-Non Finnish (NFE) AF: 0.176 AC: 194405 AN: 1107526

Other (OTH) AF: 0.180 AC: 10849 AN: 60202

GnomAD4 genome AF: 0.216 AC: 32820 AN: 151882 Hom.: 4054 Cov.: 31 AF XY: 0.213 AC XY: 15787 AN XY: 74252

African (AFR) AF: 0.331 AC: 13699 AN: 41390

American (AMR) AF: 0.175 AC: 2673 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 548 AN: 3466

East Asian (EAS) AF: 0.181 AC: 929 AN: 5138

South Asian (SAS) AF: 0.242 AC: 1162 AN: 4792

European-Finnish (FIN) AF: 0.109 AC: 1149 AN: 10588

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.178 AC: 12095 AN: 67936

Other (OTH) AF: 0.195 AC: 411 AN: 2108

Alfa AF: 0.183 Hom.: 4249

Bravo AF: 0.220

Asia WGS AF: 0.227 AC: 793 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	5.4
DANN	Benign	0.75
PhyloP100		-0.084
PromoterAI		0.033	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2242588; hg19: chr6-71012575;