chr20-62832970-C-G

Variant names:

• chr20-62832970-C-G
• rs2294993
• NM_001853.4:c.1324-50C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001853.4(COL9A3):​c.1324-50C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,531,524 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (38 hom.)
• Consequence: COL9A3 NM_001853.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.118
• Publications: 0 publications found

Genes affected

COL9A3 (HGNC:2219): (collagen type IX alpha 3 chain) This gene encodes one of the three alpha chains of type IX collagen, the major collagen component of hyaline cartilage. Type IX collagen, a heterotrimeric molecule, is usually found in tissues containing type II collagen, a fibrillar collagen. Mutations in this gene are associated with multiple epiphyseal dysplasia type 3. [provided by RefSeq, Jan 2010]

COL9A3 Gene-Disease associations (from GenCC):

• epiphyseal dysplasia, multiple, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Stickler syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Ambry Genetics, Genomics England PanelApp
• Stickler syndrome, type 6

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 20-62832970-C-G is Benign according to our data. Variant chr20-62832970-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1191846.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00127 (194/152296) while in subpopulation EAS AF = 0.0353 (183/5182). AF 95% confidence interval is 0.0311. There are 4 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001853.4. 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
	COL9A3	NM_001853.4	MANE Select	c.1324-50C>G		intron	N/A	NP_001844.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A3	ENST00000649368.1	MANE Select	c.1324-50C>G		intron	N/A	ENSP00000496793.1	Q14050
	COL9A3	ENST00000934236.1		c.1375-50C>G		intron	N/A	ENSP00000604295.1
	COL9A3	ENST00000894732.1		c.1252-50C>G		intron	N/A	ENSP00000564791.1

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 194 AN: 152178 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0352

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00288 AC: 723 AN: 250716 AF XY: 0.00265

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0374

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000795

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00116 AC: 1594 AN: 1379228 Hom.: 38 Cov.: 23 AF XY: 0.00112 AC XY: 777 AN XY: 690808

African (AFR) AF: 0.00 AC: 0 AN: 31632

American (AMR) AF: 0.0000448 AC: 2 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25620

East Asian (EAS) AF: 0.0368 AC: 1446 AN: 39318

South Asian (SAS) AF: 0.000626 AC: 53 AN: 84598

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53260

Middle Eastern (MID) AF: 0.000535 AC: 3 AN: 5610

European-Non Finnish (NFE) AF: 0.0000289 AC: 30 AN: 1037028

Other (OTH) AF: 0.00102 AC: 59 AN: 57564

GnomAD4 genome AF: 0.00127 AC: 194 AN: 152296 Hom.: 4 Cov.: 33 AF XY: 0.00146 AC XY: 109 AN XY: 74466

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.000131 AC: 2 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0353 AC: 183 AN: 5182

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000299 Hom.: 0

Bravo AF: 0.00177

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely 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	-0.94
CADD	Benign	0.11
DANN	Benign	0.67
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism

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: rs2294993; hg19: chr20-61464322; COSMIC: COSV59651212; COSMIC: COSV59651212;