rs1018440

Variant names:

• chr20-62833088-G-A
• rs1018440
• NM_001853.4:c.1368+24G>A

Variant summary

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

The ENST00000649368.1(COL9A3):​c.1368+24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,599,502 control chromosomes in the GnomAD database, including 38,790 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (7162 hom., cov: 33)
  • Exomes 𝑓: 0.20 (31628 hom.)
• Consequence: COL9A3 ENST00000649368.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.295
• Publications: 9 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=-0.89).
• BP6: Variant 20-62833088-G-A is Benign according to our data. Variant chr20-62833088-G-A is described in ClinVar as Benign. ClinVar VariationId is 258406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.488 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000649368.1. 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.1368+24G>A		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.1368+24G>A		intron	N/A	ENSP00000496793.1
	COL9A3	ENST00000462700.5	TSL:3	n.178+24G>A		intron	N/A
	COL9A3	ENST00000466192.5	TSL:2	n.1095+24G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.270 AC: 41127 AN: 152100 Hom.: 7144 Cov.: 33

Gnomad AFR AF: 0.494

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.0586

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.248

GnomAD2 exomes AF: 0.184 AC: 46055 AN: 250726 AF XY: 0.179

Gnomad AFR exome AF: 0.501

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.148

Gnomad EAS exome AF: 0.0565

Gnomad FIN exome AF: 0.209

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.189

GnomAD4 exome AF: 0.198 AC: 286257 AN: 1447284 Hom.: 31628 Cov.: 27 AF XY: 0.195 AC XY: 140248 AN XY: 720858

African (AFR) AF: 0.510 AC: 16823 AN: 33004

American (AMR) AF: 0.112 AC: 4983 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 4024 AN: 26062

East Asian (EAS) AF: 0.0487 AC: 1931 AN: 39616

South Asian (SAS) AF: 0.105 AC: 9039 AN: 86016

European-Finnish (FIN) AF: 0.202 AC: 10749 AN: 53206

Middle Eastern (MID) AF: 0.198 AC: 1136 AN: 5742

European-Non Finnish (NFE) AF: 0.206 AC: 225863 AN: 1099070

Other (OTH) AF: 0.196 AC: 11709 AN: 59884

GnomAD4 genome AF: 0.271 AC: 41189 AN: 152218 Hom.: 7162 Cov.: 33 AF XY: 0.263 AC XY: 19565 AN XY: 74436

African (AFR) AF: 0.494 AC: 20499 AN: 41500

American (AMR) AF: 0.173 AC: 2642 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 549 AN: 3470

East Asian (EAS) AF: 0.0585 AC: 303 AN: 5180

South Asian (SAS) AF: 0.107 AC: 517 AN: 4830

European-Finnish (FIN) AF: 0.206 AC: 2182 AN: 10614

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13825 AN: 68004

Other (OTH) AF: 0.245 AC: 517 AN: 2112

Alfa AF: 0.243 Hom.: 1180

Bravo AF: 0.279

Asia WGS AF: 0.104 AC: 362 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.0
DANN	Benign	0.68
PhyloP100		0.29
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: rs1018440; hg19: chr20-61464440; COSMIC: COSV59653078; COSMIC: COSV59653078;