chr20-62819981-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001853.4(COL9A3):c.308G>A(p.Arg103Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,612,462 control chromosomes in the GnomAD database, including 279 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict 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. R103W) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0096 ( 16 hom., cov: 33)

Exomes 𝑓: 0.015 ( 263 hom. )

Consequence

COL9A3
NM_001853.4 missense, splice_region

Scores

Splicing: ADA: 0.004469

Clinical Significance

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

Conservation

PhyloP100: 1.98

Publications

16 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=0.0064404905).

BP6

Variant 20-62819981-G-A is Benign according to our data. Variant chr20-62819981-G-A is described in ClinVar as Benign. ClinVar VariationId is 197734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00963 (1463/151968) while in subpopulation SAS AF = 0.0439 (211/4810). AF 95% confidence interval is 0.039. There are 16 homozygotes in GnomAd4. There are 681 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A3	NM_001853.4 link	c.308G>A	p.Arg103Gln	missense_variant, splice_region_variant	Exon 5 of 32	ENST00000649368.1	NP_001844.3	Q14050

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL9A3	ENST00000649368.1 link	c.308G>A	p.Arg103Gln	missense_variant, splice_region_variant	Exon 5 of 32		NM_001853.4	ENSP00000496793.1	Q14050
COL9A3	ENST00000452372.2 link	c.197G>A	p.Arg66Gln	missense_variant, splice_region_variant	Exon 4 of 12	5		ENSP00000394280.1	Q4VXW1
COL9A3	ENST00000477612.5 link	n.304G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 12	3
COL9A3	ENST00000489045.5 link	n.354G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 14	5

Frequencies

GnomAD3 genomes

AF:

0.00965

AC:

1465

AN:

151850

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00256

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.0229

Gnomad SAS

AF:

0.0442

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.0137

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.0136

AC:

3395

AN:

249638

AF XY:

0.0155

show subpopulations

Gnomad AFR exome

AF:

0.00149

Gnomad AMR exome

AF:

0.00269

Gnomad ASJ exome

AF:

0.00219

Gnomad EAS exome

AF:

0.0215

Gnomad FIN exome

AF:

0.00228

Gnomad NFE exome

AF:

0.0129

Gnomad OTH exome

AF:

0.00753

GnomAD4 exome

AF:

0.0150

AC:

21913

AN:

1460494

Hom.:

263

Cov.:

AF XY:

0.0158

AC XY:

11485

AN XY:

726570

show subpopulations

African (AFR)

AF:

0.00191

AC:

AN:

33480

American (AMR)

AF:

0.00271

AC:

121

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00295

AC:

AN:

26136

East Asian (EAS)

AF:

0.0188

AC:

747

AN:

39696

South Asian (SAS)

AF:

0.0417

AC:

3601

AN:

86256

European-Finnish (FIN)

AF:

0.00309

AC:

161

AN:

52130

Middle Eastern (MID)

AF:

0.0135

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0147

AC:

16339

AN:

1111942

Other (OTH)

AF:

0.0120

AC:

725

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

1247

2494

3742

4989

6236

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

660

1320

1980

2640

3300

<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:

0.00963

AC:

1463

AN:

151968

Hom.:

Cov.:

AF XY:

0.00917

AC XY:

681

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.00256

AC:

106

AN:

41480

American (AMR)

AF:

0.00288

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3470

East Asian (EAS)

AF:

0.0232

AC:

118

AN:

5090

South Asian (SAS)

AF:

0.0439

AC:

211

AN:

4810

European-Finnish (FIN)

AF:

0.00226

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0137

AC:

930

AN:

67930

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

155

232

310

387

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0130

Hom.:

Bravo

AF:

0.00826

TwinsUK

AF:

0.0151

AC:

ALSPAC

AF:

0.0176

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0133

AC:

114

ExAC

AF:

0.0145

AC:

1756

Asia WGS

AF:

0.0290

AC:

101

AN:

3478

EpiCase

AF:

0.0119

EpiControl

AF:

0.0129

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 31, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30467950) -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL9A3: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 07, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 06, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Connective tissue disorder

Benign:1

Mar 05, 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

0.099

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;T;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.79

.;T;T

MetaRNN

Benign

0.0064

T;T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

0.51

N;N;.

PhyloP100

2.0

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.21

.;N;N

REVEL

Benign

0.16

Sift

Benign

0.22

.;T;T

Sift4G

Benign

0.13

.;T;T

Polyphen

0.022

B;B;.

Vest4

0.11

MPC

0.081

ClinPred

0.013

GERP RS

3.7

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

3.1

Varity_R

0.079

gMVP

0.50

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0045

dbscSNV1_RF

Benign

0.15

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