rs16868869

Variant names:

• chr6-70272091-A-G
• rs16868869
• NM_001851.6:c.1066-3T>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.1066-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0237 in 1,610,200 control chromosomes in the GnomAD database, including 859 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (120 hom., cov: 32)
  • Exomes 𝑓: 0.023 (739 hom.)
• Consequence: COL9A1 NM_001851.6 splice_region, intron
• Scores: Splicing: ADA: 0.00003366
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.106
• Publications: 7 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=-0.73).
• BP6: Variant 6-70272091-A-G is Benign according to our data. Variant chr6-70272091-A-G is described in ClinVar as Benign. ClinVar VariationId is 258337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0972 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A1	NM_001851.6	c.1066-3T>C		splice_region_variant, intron_variant	Intron 12 of 37	ENST00000357250.11	NP_001842.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A1	ENST00000357250.11	c.1066-3T>C		splice_region_variant, intron_variant	Intron 12 of 37	1	NM_001851.6	ENSP00000349790.6

Frequencies

GnomAD3 genomes AF: 0.0341 AC: 5183 AN: 152136 Hom.: 118 Cov.: 32

Gnomad AFR AF: 0.0509

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0634

Gnomad ASJ AF: 0.0401

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.00527

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0335

GnomAD2 exomes AF: 0.0380 AC: 9473 AN: 249450 AF XY: 0.0329

Gnomad AFR exome AF: 0.0516

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.0311

Gnomad EAS exome AF: 0.0992

Gnomad FIN exome AF: 0.00597

Gnomad NFE exome AF: 0.0164

Gnomad OTH exome AF: 0.0308

GnomAD4 exome AF: 0.0226 AC: 32917 AN: 1457946 Hom.: 739 Cov.: 30 AF XY: 0.0216 AC XY: 15644 AN XY: 725532

African (AFR) AF: 0.0512 AC: 1704 AN: 33294

American (AMR) AF: 0.108 AC: 4795 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.0326 AC: 851 AN: 26076

East Asian (EAS) AF: 0.0866 AC: 3431 AN: 39614

South Asian (SAS) AF: 0.0126 AC: 1082 AN: 85982

European-Finnish (FIN) AF: 0.00663 AC: 354 AN: 53364

Middle Eastern (MID) AF: 0.0276 AC: 159 AN: 5760

European-Non Finnish (NFE) AF: 0.0170 AC: 18841 AN: 1109084

Other (OTH) AF: 0.0282 AC: 1700 AN: 60220

GnomAD4 genome AF: 0.0340 AC: 5181 AN: 152254 Hom.: 120 Cov.: 32 AF XY: 0.0336 AC XY: 2503 AN XY: 74450

African (AFR) AF: 0.0508 AC: 2109 AN: 41548

American (AMR) AF: 0.0634 AC: 970 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0401 AC: 139 AN: 3470

East Asian (EAS) AF: 0.104 AC: 541 AN: 5180

South Asian (SAS) AF: 0.0216 AC: 104 AN: 4822

European-Finnish (FIN) AF: 0.00527 AC: 56 AN: 10622

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0172 AC: 1171 AN: 68008

Other (OTH) AF: 0.0327 AC: 69 AN: 2112

Alfa AF: 0.0243 Hom.: 90

Bravo AF: 0.0420

Asia WGS AF: 0.0640 AC: 222 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 11, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:3

Aug 10, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.91
DANN	Benign	0.68
PhyloP100		0.11
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0
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: rs16868869; hg19: chr6-70981794; COSMIC: COSV57886032; COSMIC: COSV57886032;