rs2294984

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.421

Publications

9 publications found

Variant links:

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

COL9A3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A3	NM_001853.4 link	c.50G>A	p.Gly17Glu	missense_variant	Exon 1 of 32	ENST00000649368.1	NP_001844.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A3	ENST00000649368.1 link	c.50G>A	p.Gly17Glu	missense_variant	Exon 1 of 32		NM_001853.4	ENSP00000496793.1
COL9A3	ENST00000477612.5 link	n.75-453G>A		intron_variant	Intron 1 of 11	3

Frequencies

GnomAD3 genomes

AF:

0.126

AC:

19055

AN:

151338

Hom.:

1314

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.146

AC XY:

89540

AN XY:

615008

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

7707

15413

23120

30826

38533

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6162

12324

18486

24648

30810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.126

AC:

19055

AN:

151446

Hom.:

1315

Cov.:

AF XY:

0.123

AC XY:

9118

AN XY:

74006

show subpopulations

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:

AN:

292

European-Non Finnish (NFE)

AF:

0.156

AC:

10569

AN:

67712

Other (OTH)

AF:

0.121

AC:

254

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

883

1766

2650

3533

4416

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

216

432

648

864

1080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 05, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in 1000Genomes: 272/2178=12.48% -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Jun 05, 2018

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. -

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

- -

Epiphyseal dysplasia, multiple, 3

Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Connective tissue disorder

Benign:1

Jul 18, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0070

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.26

.;T

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.2

L;L

PhyloP100

0.42

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.0

.;N

REVEL

Uncertain

0.35

Sift

Benign

0.28

.;T

Sift4G

Benign

0.37

.;T

Polyphen

0.079

B;B

Vest4

0.17

MPC

0.091

ClinPred

0.00070

GERP RS

0.41

PromoterAI

-0.089

Neutral

(source)

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)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over