rs542267

Variant names:

• chr6-70230874-C-T
• rs542267
• NM_001851.6:c.2503+1709G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001851.6(COL9A1):​c.2503+1709G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0923 in 152,202 control chromosomes in the GnomAD database, including 1,517 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.092 (1517 hom., cov: 33)
• Consequence: COL9A1 NM_001851.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.305
• Publications: 0 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

ENSG00000253809 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.257 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.2503+1709G>A		intron	N/A	NP_001842.3
	COL9A1	NM_001377289.1		c.1804+1709G>A		intron	N/A	NP_001364218.1
	COL9A1	NM_078485.4		c.1774+1709G>A		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.2503+1709G>A		intron	N/A	ENSP00000349790.6
	COL9A1	ENST00000320755.12	TSL:1	c.1774+1709G>A		intron	N/A	ENSP00000315252.7
	COL9A1	ENST00000683980.2		c.1804+1709G>A		intron	N/A	ENSP00000506990.1

Frequencies

GnomAD3 genomes AF: 0.0922 AC: 14016 AN: 152084 Hom.: 1516 Cov.: 33

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0846

Gnomad ASJ AF: 0.0354

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.0184

Gnomad FIN AF: 0.00603

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.0699

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0923 AC: 14043 AN: 152202 Hom.: 1517 Cov.: 33 AF XY: 0.0902 AC XY: 6715 AN XY: 74426

African (AFR) AF: 0.261 AC: 10844 AN: 41484

American (AMR) AF: 0.0848 AC: 1296 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0354 AC: 123 AN: 3472

East Asian (EAS) AF: 0.109 AC: 563 AN: 5178

South Asian (SAS) AF: 0.0178 AC: 86 AN: 4824

European-Finnish (FIN) AF: 0.00603 AC: 64 AN: 10614

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0133 AC: 907 AN: 68024

Other (OTH) AF: 0.0691 AC: 146 AN: 2112

Alfa AF: 0.0688 Hom.: 135

Bravo AF: 0.108

Asia WGS AF: 0.0730 AC: 255 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.4
DANN	Benign	0.48
PhyloP100		-0.30
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: rs542267; hg19: chr6-70940577;