6-70300398-A-G

Variant names:

• chr6-70300398-A-G
• rs12210123
• NM_001851.6:c.89-12T>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.89-12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,544,692 control chromosomes in the GnomAD database, including 26,920 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3338 hom., cov: 31)
  • Exomes 𝑓: 0.18 (23582 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Scores: Splicing: ADA: 0.005395
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.450
• Publications: 10 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=-0.64).
• BP6: Variant 6-70300398-A-G is Benign according to our data. Variant chr6-70300398-A-G is described in ClinVar as Benign. ClinVar VariationId is 258362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A1	NM_001851.6	c.89-12T>C		intron_variant	Intron 2 of 37	ENST00000357250.11	NP_001842.3
COL9A1	NM_001377291.1	c.89-12T>C		intron_variant	Intron 2 of 10		NP_001364220.1
COL9A1	XM_011535429.4	c.89-12T>C		intron_variant	Intron 2 of 38		XP_011533731.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A1	ENST00000357250.11	c.89-12T>C		intron_variant	Intron 2 of 37	1	NM_001851.6	ENSP00000349790.6
COL9A1	ENST00000370496.3	c.89-12T>C		intron_variant	Intron 2 of 10	1		ENSP00000359527.3

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30603 AN: 151438 Hom.: 3336 Cov.: 31

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.258

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.190

GnomAD2 exomes AF: 0.168 AC: 42203 AN: 251072 AF XY: 0.169

Gnomad AFR exome AF: 0.275

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.222

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.196

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.178 AC: 248179 AN: 1393150 Hom.: 23582 Cov.: 24 AF XY: 0.178 AC XY: 123949 AN XY: 697348

African (AFR) AF: 0.284 AC: 9087 AN: 32028

American (AMR) AF: 0.106 AC: 4713 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 5639 AN: 25718

East Asian (EAS) AF: 0.000712 AC: 28 AN: 39322

South Asian (SAS) AF: 0.144 AC: 12253 AN: 84878

European-Finnish (FIN) AF: 0.201 AC: 10713 AN: 53320

Middle Eastern (MID) AF: 0.224 AC: 1262 AN: 5634

European-Non Finnish (NFE) AF: 0.185 AC: 194210 AN: 1049554

Other (OTH) AF: 0.177 AC: 10274 AN: 58070

GnomAD4 genome AF: 0.202 AC: 30611 AN: 151542 Hom.: 3338 Cov.: 31 AF XY: 0.199 AC XY: 14754 AN XY: 74058

African (AFR) AF: 0.271 AC: 11189 AN: 41290

American (AMR) AF: 0.142 AC: 2161 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 789 AN: 3464

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5184

South Asian (SAS) AF: 0.138 AC: 663 AN: 4808

European-Finnish (FIN) AF: 0.198 AC: 2051 AN: 10372

Middle Eastern (MID) AF: 0.267 AC: 78 AN: 292

European-Non Finnish (NFE) AF: 0.191 AC: 12977 AN: 67880

Other (OTH) AF: 0.189 AC: 398 AN: 2106

Alfa AF: 0.192 Hom.: 4299

Bravo AF: 0.202

Asia WGS AF: 0.0660 AC: 231 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

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 05, 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. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	18
DANN	Benign	0.89
PhyloP100		0.45
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0054
dbscSNV1_RF	Benign	0.11
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: rs12210123; hg19: chr6-71010101;