rs114458036

Variant names:

• chr20-62828988-G-C
• rs114458036
• NM_001853.4:c.1008+12G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001853.4(COL9A3):​c.1008+12G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,593,186 control chromosomes in the GnomAD database, including 33,534 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4556 hom., cov: 34)
  • Exomes 𝑓: 0.20 (28978 hom.)
• Consequence: COL9A3 NM_001853.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.67
• Publications: 4 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: Ambry Genetics, Illumina, G2P, Labcorp Genetics (formerly Invitae)
• Stickler syndrome

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 20-62828988-G-C is Benign according to our data. Variant chr20-62828988-G-C is described in ClinVar as Benign. ClinVar VariationId is 258403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.346 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A3	NM_001853.4	MANE Select	c.1008+12G>C		intron	N/A	NP_001844.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A3	ENST00000649368.1	MANE Select	c.1008+12G>C		intron	N/A	ENSP00000496793.1
	COL9A3	ENST00000463487.2	TSL:5	n.*12G>C		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35178 AN: 152098 Hom.: 4545 Cov.: 34

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.209

GnomAD2 exomes AF: 0.196 AC: 42116 AN: 214616 AF XY: 0.194

Gnomad AFR exome AF: 0.353

Gnomad AMR exome AF: 0.170

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.127

Gnomad FIN exome AF: 0.191

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.188

GnomAD4 exome AF: 0.197 AC: 284500 AN: 1440970 Hom.: 28978 Cov.: 38 AF XY: 0.197 AC XY: 140865 AN XY: 715886

African (AFR) AF: 0.366 AC: 12101 AN: 33100

American (AMR) AF: 0.172 AC: 7371 AN: 42830

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 4313 AN: 25826

East Asian (EAS) AF: 0.118 AC: 4596 AN: 38792

South Asian (SAS) AF: 0.189 AC: 15900 AN: 84290

European-Finnish (FIN) AF: 0.189 AC: 9026 AN: 47808

Middle Eastern (MID) AF: 0.216 AC: 940 AN: 4350

European-Non Finnish (NFE) AF: 0.197 AC: 218078 AN: 1104484

Other (OTH) AF: 0.205 AC: 12175 AN: 59490

GnomAD4 genome AF: 0.231 AC: 35224 AN: 152216 Hom.: 4556 Cov.: 34 AF XY: 0.228 AC XY: 16976 AN XY: 74426

African (AFR) AF: 0.350 AC: 14544 AN: 41514

American (AMR) AF: 0.184 AC: 2814 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 607 AN: 3468

East Asian (EAS) AF: 0.115 AC: 593 AN: 5174

South Asian (SAS) AF: 0.184 AC: 890 AN: 4828

European-Finnish (FIN) AF: 0.188 AC: 1993 AN: 10618

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.193 AC: 13144 AN: 67990

Other (OTH) AF: 0.208 AC: 440 AN: 2112

Alfa AF: 0.212 Hom.: 655

Bravo AF: 0.237

Asia WGS AF: 0.181 AC: 629 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 19, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.1
DANN	Benign	0.30
PhyloP100		-1.7
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: rs114458036; hg19: chr20-61460340;