NM_001851.6:c.*229T>C

Variant names:

• chr6-70216668-A-G
• rs2459555
• NM_001851.6:c.*229T>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.*229T>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 0.0646 in 506,042 control chromosomes in the GnomAD database, including 1,695 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.099 (998 hom., cov: 31)
  • Exomes 𝑓: 0.051 (697 hom.)
• Consequence: COL9A1 NM_001851.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.98
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-70216668-A-G is Benign according to our data. Variant chr6-70216668-A-G is described in ClinVar as [Benign]. Clinvar id is 1230709.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A1	NM_001851.6	c.*229T>C		3_prime_UTR_variant	Exon 38 of 38	ENST00000357250.11	NP_001842.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A1	ENST00000357250.11	c.*229T>C		3_prime_UTR_variant	Exon 38 of 38	1	NM_001851.6	ENSP00000349790.6

Frequencies

GnomAD3 genomes AF: 0.0994 AC: 14039 AN: 141236 Hom.: 999 Cov.: 31

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.0213

Gnomad AMR AF: 0.0591

Gnomad ASJ AF: 0.0386

Gnomad EAS AF: 0.00577

Gnomad SAS AF: 0.0530

Gnomad FIN AF: 0.0587

Gnomad MID AF: 0.0227

Gnomad NFE AF: 0.0637

Gnomad OTH AF: 0.0760

GnomAD4 exome AF: 0.0511 AC: 18642 AN: 364712 Hom.: 697 Cov.: 3 AF XY: 0.0501 AC XY: 9589 AN XY: 191560

African (AFR) AF: 0.191 AC: 1981 AN: 10388

American (AMR) AF: 0.0388 AC: 583 AN: 15014

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 332 AN: 11282

East Asian (EAS) AF: 0.00203 AC: 50 AN: 24638

South Asian (SAS) AF: 0.0438 AC: 1640 AN: 37428

European-Finnish (FIN) AF: 0.0475 AC: 1149 AN: 24206

Middle Eastern (MID) AF: 0.0326 AC: 52 AN: 1594

European-Non Finnish (NFE) AF: 0.0533 AC: 11673 AN: 219080

Other (OTH) AF: 0.0561 AC: 1182 AN: 21082

GnomAD4 genome AF: 0.0994 AC: 14042 AN: 141330 Hom.: 998 Cov.: 31 AF XY: 0.0984 AC XY: 6756 AN XY: 68630

African (AFR) AF: 0.203 AC: 8110 AN: 39948

American (AMR) AF: 0.0590 AC: 816 AN: 13824

Ashkenazi Jewish (ASJ) AF: 0.0386 AC: 127 AN: 3286

East Asian (EAS) AF: 0.00578 AC: 26 AN: 4496

South Asian (SAS) AF: 0.0531 AC: 236 AN: 4444

European-Finnish (FIN) AF: 0.0587 AC: 513 AN: 8736

Middle Eastern (MID) AF: 0.0176 AC: 5 AN: 284

European-Non Finnish (NFE) AF: 0.0637 AC: 4045 AN: 63522

Other (OTH) AF: 0.0751 AC: 146 AN: 1944

Alfa AF: 0.0673 Hom.: 684

Bravo AF: 0.0980

Asia WGS AF: 0.0260 AC: 91 AN: 3450

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.094
DANN	Benign	0.51
PhyloP100		-3.0
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: rs2459555; hg19: chr6-70926371;