rs35908728

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.280C>T(p.Pro94Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00988 in 1,612,860 control chromosomes in the GnomAD database, including 1,035 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. P94L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.046 ( 543 hom., cov: 33)

Exomes 𝑓: 0.0061 ( 492 hom. )

Consequence

COL9A3
NM_001853.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.324

Publications

10 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=0.0026812851).

BP6

Variant 20-62819953-C-T is Benign according to our data. Variant chr20-62819953-C-T is described in ClinVar as Benign. ClinVar VariationId is 258422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A3	NM_001853.4 link	c.280C>T	p.Pro94Ser	missense_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.280C>T	p.Pro94Ser	missense_variant	Exon 5 of 32		NM_001853.4	ENSP00000496793.1	Q14050
COL9A3	ENST00000452372.2 link	c.169C>T	p.Pro57Ser	missense_variant	Exon 4 of 12	5		ENSP00000394280.1	Q4VXW1
COL9A3	ENST00000477612.5 link	n.276C>T		non_coding_transcript_exon_variant	Exon 5 of 12	3
COL9A3	ENST00000489045.5 link	n.326C>T		non_coding_transcript_exon_variant	Exon 4 of 14	5

Frequencies

GnomAD3 genomes

AF:

0.0463

AC:

7036

AN:

152110

Hom.:

539

Cov.:

show subpopulations

Gnomad AFR

AF:

0.156

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0217

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.0157

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000809

Gnomad OTH

AF:

0.0325

GnomAD2 exomes

AF:

0.0145

AC:

3630

AN:

249832

AF XY:

0.0114

show subpopulations

Gnomad AFR exome

AF:

0.161

Gnomad AMR exome

AF:

0.0104

Gnomad ASJ exome

AF:

0.00707

Gnomad EAS exome

AF:

0.00109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000614

Gnomad OTH exome

AF:

0.00883

GnomAD4 exome

AF:

0.00607

AC:

8863

AN:

1460632

Hom.:

492

Cov.:

AF XY:

0.00565

AC XY:

4103

AN XY:

726632

show subpopulations

African (AFR)

AF:

0.163

AC:

5455

AN:

33478

American (AMR)

AF:

0.0119

AC:

530

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00696

AC:

182

AN:

26136

East Asian (EAS)

AF:

0.000831

AC:

AN:

39700

South Asian (SAS)

AF:

0.0142

AC:

1225

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52212

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000518

AC:

576

AN:

1111986

Other (OTH)

AF:

0.0133

AC:

801

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

496

993

1489

1986

2482

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

194

388

582

776

970

<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:

0.0464

AC:

7068

AN:

152228

Hom.:

543

Cov.:

AF XY:

0.0447

AC XY:

3327

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.156

AC:

6495

AN:

41516

American (AMR)

AF:

0.0216

AC:

331

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00835

AC:

AN:

3472

East Asian (EAS)

AF:

0.000965

AC:

AN:

5180

South Asian (SAS)

AF:

0.0157

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000794

AC:

AN:

67990

Other (OTH)

AF:

0.0345

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

309

618

927

1236

1545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0163

Hom.:

177

Bravo

AF:

0.0537

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.150

AC:

662

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.0171

AC:

2075

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 15, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2019

Athena Diagnostics

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

- -

not specified

Benign:2

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

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

0.069

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

T;T;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.64

.;T;T

MetaRNN

Benign

0.0027

T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.6

M;M;.

PhyloP100

0.32

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.7

.;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.16

.;T;T

Sift4G

Uncertain

0.051

.;T;D

Polyphen

0.26

B;B;.

Vest4

0.10

MPC

0.071

ClinPred

0.025

GERP RS

3.6

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

3.7

Varity_R

0.099

gMVP

0.59

Mutation Taster

=97/3

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