NM_001851.6:c.1066-36C>A

Variant names:

• chr6-70272124-G-T
• rs77357454
• NM_001851.6:c.1066-36C>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.1066-36C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0584 in 1,572,138 control chromosomes in the GnomAD database, including 3,107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (243 hom., cov: 32)
  • Exomes 𝑓: 0.060 (2864 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.354
• Publications: 5 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: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• epiphyseal dysplasia, multiple, 6

  Inheritance: Unknown, AD, AR Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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=-0.85).
• BP6: Variant 6-70272124-G-T is Benign according to our data. Variant chr6-70272124-G-T is described in ClinVar as Benign. ClinVar VariationId is 258336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0686 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.1066-36C>A		intron	N/A	NP_001842.3
	COL9A1	NM_001377289.1		c.337-36C>A		intron	N/A	NP_001364218.1	A0A804HIB6
	COL9A1	NM_078485.4		c.337-36C>A		intron	N/A	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.1066-36C>A		intron	N/A	ENSP00000349790.6	P20849-1
	COL9A1	ENST00000320755.12	TSL:1	c.337-36C>A		intron	N/A	ENSP00000315252.7	P20849-2
	COL9A1	ENST00000683980.2		c.337-36C>A		intron	N/A	ENSP00000506990.1	A0A804HIB6

Frequencies

GnomAD3 genomes AF: 0.0453 AC: 6875 AN: 151910 Hom.: 243 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.0323

Gnomad ASJ AF: 0.0542

Gnomad EAS AF: 0.00521

Gnomad SAS AF: 0.0357

Gnomad FIN AF: 0.0556

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0702

Gnomad OTH AF: 0.0364

GnomAD2 exomes AF: 0.0472 AC: 11402 AN: 241596 AF XY: 0.0480

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.0228

Gnomad ASJ exome AF: 0.0512

Gnomad EAS exome AF: 0.00404

Gnomad FIN exome AF: 0.0620

Gnomad NFE exome AF: 0.0675

Gnomad OTH exome AF: 0.0494

GnomAD4 exome AF: 0.0598 AC: 84935 AN: 1420108 Hom.: 2864 Cov.: 26 AF XY: 0.0596 AC XY: 42205 AN XY: 708212

African (AFR) AF: 0.00939 AC: 301 AN: 32054

American (AMR) AF: 0.0237 AC: 1042 AN: 44050

Ashkenazi Jewish (ASJ) AF: 0.0530 AC: 1360 AN: 25646

East Asian (EAS) AF: 0.00198 AC: 77 AN: 38882

South Asian (SAS) AF: 0.0339 AC: 2865 AN: 84488

European-Finnish (FIN) AF: 0.0652 AC: 3433 AN: 52624

Middle Eastern (MID) AF: 0.0269 AC: 151 AN: 5608

European-Non Finnish (NFE) AF: 0.0674 AC: 72694 AN: 1078036

Other (OTH) AF: 0.0513 AC: 3012 AN: 58720

GnomAD4 genome AF: 0.0452 AC: 6876 AN: 152030 Hom.: 243 Cov.: 32 AF XY: 0.0437 AC XY: 3247 AN XY: 74310

African (AFR) AF: 0.0115 AC: 479 AN: 41504

American (AMR) AF: 0.0322 AC: 492 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0542 AC: 188 AN: 3468

East Asian (EAS) AF: 0.00522 AC: 27 AN: 5168

South Asian (SAS) AF: 0.0363 AC: 174 AN: 4792

European-Finnish (FIN) AF: 0.0556 AC: 588 AN: 10570

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0702 AC: 4773 AN: 67948

Other (OTH) AF: 0.0360 AC: 76 AN: 2112

Alfa AF: 0.0613 Hom.: 107

Bravo AF: 0.0399

Asia WGS AF: 0.0190 AC: 67 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.1
DANN	Benign	0.32
PhyloP100		0.35
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: rs77357454; hg19: chr6-70981827; COSMIC: COSV57878864; COSMIC: COSV57878864;