rs61734651

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.307C>T(p.Arg103Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0592 in 1,612,252 control chromosomes in the GnomAD database, including 3,307 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R103Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.045 ( 214 hom., cov: 33)

Exomes 𝑓: 0.061 ( 3093 hom. )

Consequence

COL9A3
NM_001853.4 missense, splice_region

Scores

Splicing: ADA: 0.7530

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 0.939

Publications

43 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=0.0063285828).

BP6

Variant 20-62819980-C-T is Benign according to our data. Variant chr20-62819980-C-T is described in ClinVar as Benign. ClinVar VariationId is 17139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A3	NM_001853.4 link	c.307C>T	p.Arg103Trp	missense_variant, splice_region_variant	Exon 5 of 32	ENST00000649368.1	NP_001844.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
COL9A3	ENST00000649368.1 link	c.307C>T	p.Arg103Trp	missense_variant, splice_region_variant	Exon 5 of 32		NM_001853.4	ENSP00000496793.1
COL9A3	ENST00000452372.2 link	c.196C>T	p.Arg66Trp	missense_variant, splice_region_variant	Exon 4 of 12	5		ENSP00000394280.1
COL9A3	ENST00000477612.5 link	n.303C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 12	3
COL9A3	ENST00000489045.5 link	n.353C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 14	5

Frequencies

GnomAD3 genomes

AF:

0.0450

AC:

6823

AN:

151698

Hom.:

214

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0120

Gnomad AMI

AF:

0.0352

Gnomad AMR

AF:

0.0370

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.000587

Gnomad SAS

AF:

0.0295

Gnomad FIN

AF:

0.0957

Gnomad MID

AF:

0.0446

Gnomad NFE

AF:

0.0650

Gnomad OTH

AF:

0.0459

GnomAD2 exomes

AF:

0.0474

AC:

11845

AN:

249634

AF XY:

0.0488

show subpopulations

Gnomad AFR exome

AF:

0.0125

Gnomad AMR exome

AF:

0.0214

Gnomad ASJ exome

AF:

0.0183

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0968

Gnomad NFE exome

AF:

0.0655

Gnomad OTH exome

AF:

0.0553

GnomAD4 exome

AF:

0.0607

AC:

88695

AN:

1460438

Hom.:

3093

Cov.:

AF XY:

0.0602

AC XY:

43731

AN XY:

726546

show subpopulations

African (AFR)

AF:

0.00941

AC:

315

AN:

33480

American (AMR)

AF:

0.0223

AC:

995

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0196

AC:

513

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39698

South Asian (SAS)

AF:

0.0326

AC:

2808

AN:

86252

European-Finnish (FIN)

AF:

0.0933

AC:

4866

AN:

52140

Middle Eastern (MID)

AF:

0.0317

AC:

183

AN:

5764

European-Non Finnish (NFE)

AF:

0.0684

AC:

76088

AN:

1111880

Other (OTH)

AF:

0.0484

AC:

2922

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

4584

9168

13751

18335

22919

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2796

5592

8388

11184

13980

<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:

0.0449

AC:

6820

AN:

151814

Hom.:

214

Cov.:

AF XY:

0.0449

AC XY:

3333

AN XY:

74184

show subpopulations

African (AFR)

AF:

0.0119

AC:

494

AN:

41432

American (AMR)

AF:

0.0370

AC:

565

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

AN:

3468

East Asian (EAS)

AF:

0.000588

AC:

AN:

5098

South Asian (SAS)

AF:

0.0296

AC:

142

AN:

4802

European-Finnish (FIN)

AF:

0.0957

AC:

1011

AN:

10566

Middle Eastern (MID)

AF:

0.0342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0650

AC:

4410

AN:

67870

Other (OTH)

AF:

0.0454

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

335

670

1005

1340

1675

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

240

320

400

<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:

0.0549

Hom.:

254

Bravo

AF:

0.0391

TwinsUK

AF:

0.0690

AC:

256

ALSPAC

AF:

0.0651

AC:

251

ESP6500AA

AF:

0.0145

AC:

ESP6500EA

AF:

0.0672

AC:

578

ExAC

AF:

0.0475

AC:

5759

Asia WGS

AF:

0.00982

AC:

AN:

3478

EpiCase

AF:

0.0583

EpiControl

AF:

0.0598

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Feb 05, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 05, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Genome Diagnostics Laboratory, Amsterdam University 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

- -

Stickler syndrome

Benign:1

Apr 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

- -

Intervertebral disc disease, susceptibility to

Other:1

Apr 11, 2001

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;D;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Benign

0.71

LIST_S2

Pathogenic

0.97

.;D;D

MetaRNN

Benign

0.0063

T;T;T

MetaSVM

Uncertain

0.0011

MutationAssessor

Uncertain

2.4

M;M;.

PhyloP100

0.94

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.2

.;D;D

REVEL

Uncertain

0.50

Sift

Uncertain

0.0040

.;D;D

Sift4G

Uncertain

0.0030

.;D;D

Polyphen

1.0

D;D;.

Vest4

0.17

MPC

0.073

ClinPred

0.014

GERP RS

3.6

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.29

gMVP

0.65

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.75

dbscSNV1_RF

Benign

0.18

SpliceAI score (max)

0.010

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