rs537940

Variant names:

• chr6-70255404-A-T
• rs537940
• NM_001851.6:c.1504-14T>A

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.1504-14T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00746 in 1,613,222 control chromosomes in the GnomAD database, including 731 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (405 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (326 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.839
• Publications: 1 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=-0.74).
• BP6: Variant 6-70255404-A-T is Benign according to our data. Variant chr6-70255404-A-T is described in ClinVar as Benign. ClinVar VariationId is 258343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 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.1504-14T>A		intron	N/A	NP_001842.3
	COL9A1	NM_001377289.1		c.775-14T>A		intron	N/A	NP_001364218.1
	COL9A1	NM_078485.4		c.775-14T>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.1504-14T>A		intron	N/A	ENSP00000349790.6
	COL9A1	ENST00000320755.12	TSL:1	c.775-14T>A		intron	N/A	ENSP00000315252.7
	COL9A1	ENST00000683980.2		c.775-14T>A		intron	N/A	ENSP00000506990.1

Frequencies

GnomAD3 genomes AF: 0.0391 AC: 5955 AN: 152180 Hom.: 404 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0191

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0297

GnomAD2 exomes AF: 0.0105 AC: 2631 AN: 251052 AF XY: 0.00745

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.00810

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000485

Gnomad OTH exome AF: 0.00637

GnomAD4 exome AF: 0.00415 AC: 6066 AN: 1460924 Hom.: 326 Cov.: 31 AF XY: 0.00350 AC XY: 2542 AN XY: 726860

African (AFR) AF: 0.137 AC: 4584 AN: 33410

American (AMR) AF: 0.00861 AC: 385 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00799 AC: 46 AN: 5754

European-Non Finnish (NFE) AF: 0.000354 AC: 393 AN: 1111222

Other (OTH) AF: 0.0103 AC: 620 AN: 60384

GnomAD4 genome AF: 0.0392 AC: 5964 AN: 152298 Hom.: 405 Cov.: 32 AF XY: 0.0369 AC XY: 2751 AN XY: 74470

African (AFR) AF: 0.134 AC: 5570 AN: 41540

American (AMR) AF: 0.0190 AC: 291 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68038

Other (OTH) AF: 0.0294 AC: 62 AN: 2112

Alfa AF: 0.0208 Hom.: 33

Bravo AF: 0.0456

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.80
PhyloP100		0.84
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs537940; hg19: chr6-70965107;