rs6935778

Variant names:

• chr6-70269621-A-G
• rs6935778
• NM_001851.6:c.1230+12T>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.1230+12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,569,944 control chromosomes in the GnomAD database, including 25,837 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2025 hom., cov: 32)
  • Exomes 𝑓: 0.18 (23812 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.257
• 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):

• 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=-0.57).
• BP6: Variant 6-70269621-A-G is Benign according to our data. Variant chr6-70269621-A-G is described in ClinVar as Benign. ClinVar VariationId is 258341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.201 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.1230+12T>C		intron	N/A	NP_001842.3
	COL9A1	NM_001377289.1		c.501+12T>C		intron	N/A	NP_001364218.1
	COL9A1	NM_078485.4		c.501+12T>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.1230+12T>C		intron	N/A	ENSP00000349790.6
	COL9A1	ENST00000320755.12	TSL:1	c.501+12T>C		intron	N/A	ENSP00000315252.7
	COL9A1	ENST00000683980.2		c.501+12T>C		intron	N/A	ENSP00000506990.1

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23515 AN: 152108 Hom.: 2026 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0708

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.154

GnomAD2 exomes AF: 0.149 AC: 37200 AN: 250410 AF XY: 0.151

Gnomad AFR exome AF: 0.0994

Gnomad AMR exome AF: 0.0877

Gnomad ASJ exome AF: 0.201

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.207

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.176 AC: 248821 AN: 1417718 Hom.: 23812 Cov.: 26 AF XY: 0.174 AC XY: 122970 AN XY: 708098

African (AFR) AF: 0.0986 AC: 3231 AN: 32780

American (AMR) AF: 0.0921 AC: 4111 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 5123 AN: 25788

East Asian (EAS) AF: 0.000734 AC: 29 AN: 39488

South Asian (SAS) AF: 0.0784 AC: 6704 AN: 85482

European-Finnish (FIN) AF: 0.184 AC: 9821 AN: 53312

Middle Eastern (MID) AF: 0.177 AC: 1002 AN: 5676

European-Non Finnish (NFE) AF: 0.195 AC: 209123 AN: 1071538

Other (OTH) AF: 0.164 AC: 9677 AN: 58996

GnomAD4 genome AF: 0.154 AC: 23516 AN: 152226 Hom.: 2025 Cov.: 32 AF XY: 0.152 AC XY: 11339 AN XY: 74422

African (AFR) AF: 0.100 AC: 4173 AN: 41552

American (AMR) AF: 0.129 AC: 1967 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 717 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5186

South Asian (SAS) AF: 0.0711 AC: 343 AN: 4824

European-Finnish (FIN) AF: 0.185 AC: 1958 AN: 10586

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.204 AC: 13857 AN: 67992

Other (OTH) AF: 0.152 AC: 322 AN: 2112

Alfa AF: 0.174 Hom.: 647

Bravo AF: 0.149

Asia WGS AF: 0.0390 AC: 138 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Epiphyseal dysplasia, multiple, 6 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.85
PhyloP100		0.26
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: rs6935778; hg19: chr6-70979324;