rs1064250

Variant names:

• chr6-70216631-A-G
• rs1064250
• NM_001851.6:c.*266T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001851.6(COL9A1):​c.*266T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 483,742 control chromosomes in the GnomAD database, including 38,744 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.41 (12629 hom., cov: 31)
  • Exomes 𝑓: 0.38 (26115 hom.)
• Consequence: COL9A1 NM_001851.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.733
• Publications: 9 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):

• Stickler syndrome, type 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, ClinGen, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• epiphyseal dysplasia, multiple, 6

  Inheritance: Unknown, AR, AD Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-70216631-A-G is Benign according to our data. Variant chr6-70216631-A-G is described in ClinVar as Benign. ClinVar VariationId is 1271891.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.447 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A1	NM_001851.6	MANE Select	c.*266T>C		3_prime_UTR	Exon 38 of 38	NP_001842.3
	COL9A1	NM_001377289.1		c.*266T>C		3_prime_UTR	Exon 33 of 33	NP_001364218.1	A0A804HIB6
	COL9A1	NM_078485.4		c.*266T>C		3_prime_UTR	Exon 32 of 32	NP_511040.2	P20849-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A1	ENST00000357250.11	TSL:1 MANE Select	c.*266T>C		3_prime_UTR	Exon 38 of 38	ENSP00000349790.6	P20849-1
	COL9A1	ENST00000320755.12	TSL:1	c.*266T>C		3_prime_UTR	Exon 32 of 32	ENSP00000315252.7	P20849-2
	COL9A1	ENST00000683980.2		c.*266T>C		3_prime_UTR	Exon 33 of 33	ENSP00000506990.1	A0A804HIB6

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61254 AN: 150504 Hom.: 12606 Cov.: 31

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.549

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.341

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.423

GnomAD4 exome AF: 0.382 AC: 127279 AN: 333122 Hom.: 26115 Cov.: 2 AF XY: 0.384 AC XY: 67606 AN XY: 175988

African (AFR) AF: 0.436 AC: 4279 AN: 9822

American (AMR) AF: 0.382 AC: 5588 AN: 14620

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 5552 AN: 10092

East Asian (EAS) AF: 0.238 AC: 5071 AN: 21312

South Asian (SAS) AF: 0.412 AC: 17016 AN: 41292

European-Finnish (FIN) AF: 0.323 AC: 5801 AN: 17942

Middle Eastern (MID) AF: 0.484 AC: 683 AN: 1410

European-Non Finnish (NFE) AF: 0.383 AC: 75740 AN: 197664

Other (OTH) AF: 0.398 AC: 7549 AN: 18968

GnomAD4 genome AF: 0.407 AC: 61308 AN: 150620 Hom.: 12629 Cov.: 31 AF XY: 0.401 AC XY: 29451 AN XY: 73428

African (AFR) AF: 0.453 AC: 18602 AN: 41108

American (AMR) AF: 0.403 AC: 6035 AN: 14986

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 1903 AN: 3464

East Asian (EAS) AF: 0.226 AC: 1144 AN: 5062

South Asian (SAS) AF: 0.417 AC: 1980 AN: 4750

European-Finnish (FIN) AF: 0.341 AC: 3498 AN: 10260

Middle Eastern (MID) AF: 0.497 AC: 145 AN: 292

European-Non Finnish (NFE) AF: 0.395 AC: 26760 AN: 67712

Other (OTH) AF: 0.422 AC: 879 AN: 2082

Alfa AF: 0.406 Hom.: 16593

Bravo AF: 0.409

Asia WGS AF: 0.306 AC: 1069 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.0
DANN	Benign	0.57
PhyloP100		0.73
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: rs1064250; hg19: chr6-70926334; COSMIC: COSV57893021; COSMIC: COSV57893021;