chr6-70281062-G-C

Variant names:

• chr6-70281062-G-C
• rs6928611
• NM_001851.6:c.877-23C>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.877-23C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0672 in 1,598,954 control chromosomes in the GnomAD database, including 3,916 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (397 hom., cov: 31)
  • Exomes 𝑓: 0.067 (3519 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0390
• Publications: 5 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=-0.83).
• BP6: Variant 6-70281062-G-C is Benign according to our data. Variant chr6-70281062-G-C is described in ClinVar as Benign. ClinVar VariationId is 677878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.08 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.877-23C>G		intron	N/A	NP_001842.3
	COL9A1	NM_001377289.1		c.148-23C>G		intron	N/A	NP_001364218.1	A0A804HIB6
	COL9A1	NM_078485.4		c.148-23C>G		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.877-23C>G		intron	N/A	ENSP00000349790.6	P20849-1
	COL9A1	ENST00000320755.12	TSL:1	c.148-23C>G		intron	N/A	ENSP00000315252.7	P20849-2
	COL9A1	ENST00000370496.3	TSL:1	c.877-23C>G		intron	N/A	ENSP00000359527.3	P20849-3

Frequencies

GnomAD3 genomes AF: 0.0706 AC: 10714 AN: 151860 Hom.: 397 Cov.: 31

Gnomad AFR AF: 0.0825

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0756

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.0361

Gnomad SAS AF: 0.0758

Gnomad FIN AF: 0.0193

Gnomad MID AF: 0.153

Gnomad NFE AF: 0.0688

Gnomad OTH AF: 0.0808

GnomAD2 exomes AF: 0.0682 AC: 16255 AN: 238254 AF XY: 0.0689

Gnomad AFR exome AF: 0.0826

Gnomad AMR exome AF: 0.0877

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.0423

Gnomad FIN exome AF: 0.0196

Gnomad NFE exome AF: 0.0671

Gnomad OTH exome AF: 0.0759

GnomAD4 exome AF: 0.0669 AC: 96753 AN: 1446978 Hom.: 3519 Cov.: 33 AF XY: 0.0678 AC XY: 48796 AN XY: 719990

African (AFR) AF: 0.0822 AC: 2672 AN: 32514

American (AMR) AF: 0.0866 AC: 3686 AN: 42554

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3002 AN: 25292

East Asian (EAS) AF: 0.0371 AC: 1469 AN: 39624

South Asian (SAS) AF: 0.0745 AC: 6337 AN: 85096

European-Finnish (FIN) AF: 0.0214 AC: 1126 AN: 52554

Middle Eastern (MID) AF: 0.129 AC: 731 AN: 5648

European-Non Finnish (NFE) AF: 0.0664 AC: 73359 AN: 1104160

Other (OTH) AF: 0.0734 AC: 4371 AN: 59536

GnomAD4 genome AF: 0.0705 AC: 10713 AN: 151976 Hom.: 397 Cov.: 31 AF XY: 0.0681 AC XY: 5056 AN XY: 74290

African (AFR) AF: 0.0823 AC: 3414 AN: 41458

American (AMR) AF: 0.0755 AC: 1154 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 406 AN: 3464

East Asian (EAS) AF: 0.0361 AC: 184 AN: 5090

South Asian (SAS) AF: 0.0759 AC: 365 AN: 4812

European-Finnish (FIN) AF: 0.0193 AC: 205 AN: 10606

Middle Eastern (MID) AF: 0.158 AC: 46 AN: 292

European-Non Finnish (NFE) AF: 0.0688 AC: 4672 AN: 67944

Other (OTH) AF: 0.0790 AC: 167 AN: 2114

Alfa AF: 0.0749 Hom.: 84

Bravo AF: 0.0774

Asia WGS AF: 0.0570 AC: 198 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.39
DANN	Benign	0.44
PhyloP100		0.039
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: rs6928611; hg19: chr6-70990765;