NM_001851.6:c.975+45G>A

Variant names:

• chr6-70280767-C-T
• rs7764822
• NM_001851.6:c.975+45G>A

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.975+45G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,585,528 control chromosomes in the GnomAD database, including 30,348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3750 hom., cov: 31)
  • Exomes 𝑓: 0.19 (26598 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.108
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-70280767-C-T is Benign according to our data. Variant chr6-70280767-C-T is described in ClinVar as Benign. ClinVar VariationId is 258363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.295 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A1	NM_001851.6	MANE Select	c.975+45G>A		intron	N/A	NP_001842.3
	COL9A1	NM_001377289.1		c.246+45G>A		intron	N/A	NP_001364218.1	A0A804HIB6
	COL9A1	NM_078485.4		c.246+45G>A		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+45G>A		intron	N/A	ENSP00000349790.6	P20849-1
	COL9A1	ENST00000320755.12	TSL:1	c.246+45G>A		intron	N/A	ENSP00000315252.7	P20849-2
	COL9A1	ENST00000370496.3	TSL:1	c.975+45G>A		intron	N/A	ENSP00000359527.3	P20849-3

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32245 AN: 151724 Hom.: 3748 Cov.: 31

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.256

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.215

GnomAD2 exomes AF: 0.166 AC: 34682 AN: 209318 AF XY: 0.166

Gnomad AFR exome AF: 0.303

Gnomad AMR exome AF: 0.110

Gnomad ASJ exome AF: 0.204

Gnomad EAS exome AF: 0.000703

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.199

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.187 AC: 267488 AN: 1433686 Hom.: 26598 Cov.: 32 AF XY: 0.185 AC XY: 131409 AN XY: 711596

African (AFR) AF: 0.310 AC: 10092 AN: 32600

American (AMR) AF: 0.116 AC: 4818 AN: 41408

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 5216 AN: 25676

East Asian (EAS) AF: 0.000835 AC: 32 AN: 38336

South Asian (SAS) AF: 0.128 AC: 10615 AN: 82996

European-Finnish (FIN) AF: 0.187 AC: 9594 AN: 51334

Middle Eastern (MID) AF: 0.229 AC: 1245 AN: 5426

European-Non Finnish (NFE) AF: 0.196 AC: 214867 AN: 1096550

Other (OTH) AF: 0.185 AC: 11009 AN: 59360

GnomAD4 genome AF: 0.212 AC: 32259 AN: 151842 Hom.: 3750 Cov.: 31 AF XY: 0.210 AC XY: 15601 AN XY: 74252

African (AFR) AF: 0.299 AC: 12383 AN: 41360

American (AMR) AF: 0.160 AC: 2440 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 728 AN: 3470

East Asian (EAS) AF: 0.00175 AC: 9 AN: 5148

South Asian (SAS) AF: 0.123 AC: 593 AN: 4808

European-Finnish (FIN) AF: 0.187 AC: 1982 AN: 10572

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.197 AC: 13372 AN: 67896

Other (OTH) AF: 0.213 AC: 447 AN: 2098

Alfa AF: 0.203 Hom.: 622

Bravo AF: 0.215

Asia WGS AF: 0.0670 AC: 237 AN: 3478

ClinVar

ClinVar submissions

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	-0.82
CADD	Benign	6.7
DANN	Benign	0.57
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7764822; hg19: chr6-70990470; COSMIC: COSV57894031; COSMIC: COSV57894031;