rs2294984

Variant names:

• chr20-62817114-G-A
• rs2294984
• NM_001853.4:c.50G>A

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.50G>A​(p.Gly17Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,399,514 control chromosomes in the GnomAD database, including 15,911 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G17R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.13 (1315 hom., cov: 33)
  • Exomes 𝑓: 0.15 (14596 hom.)
• Consequence: COL9A3 NM_001853.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.421
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021308362).
• BP6: Variant 20-62817114-G-A is Benign according to our data. Variant chr20-62817114-G-A is described in ClinVar as Benign. ClinVar VariationId is 193218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.154 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A3	NM_001853.4	MANE Select	c.50G>A	p.Gly17Glu	missense	Exon 1 of 32	NP_001844.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A3	ENST00000649368.1	MANE Select	c.50G>A	p.Gly17Glu	missense	Exon 1 of 32	ENSP00000496793.1	Q14050
	COL9A3	ENST00000934236.1		c.50G>A	p.Gly17Glu	missense	Exon 1 of 33	ENSP00000604295.1
	COL9A3	ENST00000894732.1		c.50G>A	p.Gly17Glu	missense	Exon 1 of 31	ENSP00000564791.1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19055 AN: 151338 Hom.: 1314 Cov.: 33

Gnomad AFR AF: 0.0994

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0977

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.0346

Gnomad SAS AF: 0.0700

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.123

GnomAD2 exomes AF: 0.105 AC: 7842 AN: 74786 AF XY: 0.106

Gnomad AFR exome AF: 0.0977

Gnomad AMR exome AF: 0.0555

Gnomad ASJ exome AF: 0.0988

Gnomad EAS exome AF: 0.0366

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.148 AC: 184420 AN: 1248068 Hom.: 14596 Cov.: 31 AF XY: 0.146 AC XY: 89540 AN XY: 615008

African (AFR) AF: 0.0983 AC: 2466 AN: 25084

American (AMR) AF: 0.0650 AC: 1576 AN: 24234

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2149 AN: 20468

East Asian (EAS) AF: 0.0227 AC: 563 AN: 24782

South Asian (SAS) AF: 0.0677 AC: 4510 AN: 66604

European-Finnish (FIN) AF: 0.154 AC: 4647 AN: 30132

Middle Eastern (MID) AF: 0.110 AC: 388 AN: 3522

European-Non Finnish (NFE) AF: 0.161 AC: 161688 AN: 1003328

Other (OTH) AF: 0.129 AC: 6433 AN: 49914

GnomAD4 genome AF: 0.126 AC: 19055 AN: 151446 Hom.: 1315 Cov.: 33 AF XY: 0.123 AC XY: 9118 AN XY: 74006

African (AFR) AF: 0.0993 AC: 4116 AN: 41466

American (AMR) AF: 0.0977 AC: 1486 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 357 AN: 3462

East Asian (EAS) AF: 0.0343 AC: 177 AN: 5162

South Asian (SAS) AF: 0.0702 AC: 339 AN: 4826

European-Finnish (FIN) AF: 0.161 AC: 1658 AN: 10312

Middle Eastern (MID) AF: 0.106 AC: 31 AN: 292

European-Non Finnish (NFE) AF: 0.156 AC: 10569 AN: 67712

Other (OTH) AF: 0.121 AC: 254 AN: 2098

Alfa AF: 0.134 Hom.: 183

Bravo AF: 0.120

TwinsUK AF: 0.166 AC: 616

ALSPAC AF: 0.159 AC: 611

ExAC AF: 0.0663 AC: 4505

Asia WGS AF: 0.0400 AC: 129 AN: 3212

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	1	Connective tissue disorder (1)
-	-	1	Epiphyseal dysplasia, multiple, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.0070	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.42
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.35
Sift	Benign	0.28	T
Sift4G	Benign	0.37	T
Polyphen		0.079	B
Vest4		0.17
MPC		0.091
ClinPred		0.00070	T
GERP RS		0.41
PromoterAI		-0.089	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.086
gMVP		0.58
Mutation Taster		=99/1	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: rs2294984; hg19: chr20-61448466; COSMIC: COSV51702900; COSMIC: COSV51702900;