6-70252341-A-G

Variant names:

• chr6-70252341-A-G
• rs519068
• NM_001851.6:c.1765-26T>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.1765-26T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.478 in 1,606,610 control chromosomes in the GnomAD database, including 186,885 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (17648 hom., cov: 32)
  • Exomes 𝑓: 0.48 (169237 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.243
• Publications: 12 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=-0.83).
• BP6: Variant 6-70252341-A-G is Benign according to our data. Variant chr6-70252341-A-G is described in ClinVar as Benign. ClinVar VariationId is 258352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.512 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.1765-26T>C		intron	N/A	NP_001842.3
	COL9A1	NM_001377289.1		c.1066-26T>C		intron	N/A	NP_001364218.1
	COL9A1	NM_078485.4		c.1036-26T>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.1765-26T>C		intron	N/A	ENSP00000349790.6
	COL9A1	ENST00000320755.12	TSL:1	c.1036-26T>C		intron	N/A	ENSP00000315252.7
	COL9A1	ENST00000683980.2		c.1066-26T>C		intron	N/A	ENSP00000506990.1

Frequencies

GnomAD3 genomes AF: 0.477 AC: 72445 AN: 151912 Hom.: 17629 Cov.: 32

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.485

Gnomad EAS AF: 0.289

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.446

GnomAD2 exomes AF: 0.441 AC: 110556 AN: 250532 AF XY: 0.442

Gnomad AFR exome AF: 0.522

Gnomad AMR exome AF: 0.327

Gnomad ASJ exome AF: 0.484

Gnomad EAS exome AF: 0.287

Gnomad FIN exome AF: 0.472

Gnomad NFE exome AF: 0.500

Gnomad OTH exome AF: 0.452

GnomAD4 exome AF: 0.478 AC: 695932 AN: 1454580 Hom.: 169237 Cov.: 31 AF XY: 0.475 AC XY: 343983 AN XY: 724134

African (AFR) AF: 0.518 AC: 17275 AN: 33324

American (AMR) AF: 0.331 AC: 14787 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.481 AC: 12552 AN: 26094

East Asian (EAS) AF: 0.274 AC: 10862 AN: 39652

South Asian (SAS) AF: 0.370 AC: 31837 AN: 86122

European-Finnish (FIN) AF: 0.481 AC: 25683 AN: 53380

Middle Eastern (MID) AF: 0.441 AC: 2535 AN: 5748

European-Non Finnish (NFE) AF: 0.500 AC: 552335 AN: 1105414

Other (OTH) AF: 0.466 AC: 28066 AN: 60170

GnomAD4 genome AF: 0.477 AC: 72509 AN: 152030 Hom.: 17648 Cov.: 32 AF XY: 0.471 AC XY: 34985 AN XY: 74304

African (AFR) AF: 0.518 AC: 21457 AN: 41450

American (AMR) AF: 0.375 AC: 5738 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.485 AC: 1682 AN: 3470

East Asian (EAS) AF: 0.287 AC: 1486 AN: 5172

South Asian (SAS) AF: 0.353 AC: 1701 AN: 4818

European-Finnish (FIN) AF: 0.472 AC: 4981 AN: 10560

Middle Eastern (MID) AF: 0.442 AC: 129 AN: 292

European-Non Finnish (NFE) AF: 0.500 AC: 33999 AN: 67946

Other (OTH) AF: 0.445 AC: 941 AN: 2114

Alfa AF: 0.486 Hom.: 24490

Bravo AF: 0.474

Asia WGS AF: 0.332 AC: 1155 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Epiphyseal dysplasia, multiple, 6 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.8
DANN	Benign	0.66
PhyloP100		0.24
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: rs519068; hg19: chr6-70962044; COSMIC: COSV57889978;