chr6-70241400-A-G

Variant names:

• chr6-70241400-A-G
• rs13202029
• NM_001851.6:c.2034+19T>C

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.2034+19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,597,660 control chromosomes in the GnomAD database, including 28,676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2016 hom., cov: 32)
  • Exomes 𝑓: 0.18 (26660 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.908
• Publications: 6 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

ENSG00000253809 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 6-70241400-A-G is Benign according to our data. Variant chr6-70241400-A-G is described in ClinVar as Benign. ClinVar VariationId is 258354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.207 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.2034+19T>C		intron	N/A	NP_001842.3
	COL9A1	NM_001377289.1		c.1335+19T>C		intron	N/A	NP_001364218.1
	COL9A1	NM_078485.4		c.1305+19T>C		intron	N/A	NP_511040.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A1	ENST00000357250.11	TSL:1 MANE Select	c.2034+19T>C		intron	N/A	ENSP00000349790.6
	COL9A1	ENST00000320755.12	TSL:1	c.1305+19T>C		intron	N/A	ENSP00000315252.7
	COL9A1	ENST00000683980.2		c.1335+19T>C		intron	N/A	ENSP00000506990.1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22405 AN: 152136 Hom.: 2016 Cov.: 32

Gnomad AFR AF: 0.0621

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0704

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.149

GnomAD2 exomes AF: 0.150 AC: 37617 AN: 251336 AF XY: 0.153

Gnomad AFR exome AF: 0.0606

Gnomad AMR exome AF: 0.0867

Gnomad ASJ exome AF: 0.209

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.182

Gnomad NFE exome AF: 0.213

Gnomad OTH exome AF: 0.168

GnomAD4 exome AF: 0.184 AC: 265252 AN: 1445406 Hom.: 26660 Cov.: 28 AF XY: 0.181 AC XY: 130686 AN XY: 720234

African (AFR) AF: 0.0561 AC: 1866 AN: 33258

American (AMR) AF: 0.0901 AC: 4029 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 5355 AN: 26004

East Asian (EAS) AF: 0.000656 AC: 26 AN: 39662

South Asian (SAS) AF: 0.0804 AC: 6919 AN: 86042

European-Finnish (FIN) AF: 0.188 AC: 10054 AN: 53394

Middle Eastern (MID) AF: 0.162 AC: 927 AN: 5736

European-Non Finnish (NFE) AF: 0.206 AC: 226097 AN: 1096748

Other (OTH) AF: 0.167 AC: 9979 AN: 59856

GnomAD4 genome AF: 0.147 AC: 22405 AN: 152254 Hom.: 2016 Cov.: 32 AF XY: 0.145 AC XY: 10801 AN XY: 74438

African (AFR) AF: 0.0620 AC: 2575 AN: 41556

American (AMR) AF: 0.128 AC: 1960 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 741 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5190

South Asian (SAS) AF: 0.0710 AC: 343 AN: 4828

European-Finnish (FIN) AF: 0.189 AC: 2001 AN: 10600

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14300 AN: 68002

Other (OTH) AF: 0.148 AC: 311 AN: 2108

Alfa AF: 0.139 Hom.: 454

Bravo AF: 0.140

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Epiphyseal dysplasia, multiple, 6 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.3
DANN	Benign	0.55
PhyloP100		0.91
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: rs13202029; hg19: chr6-70951103;