rs45628843

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.887C>T(p.Pro296Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0506 in 1,612,860 control chromosomes in the GnomAD database, including 2,435 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P296P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.040 ( 197 hom., cov: 33)

Exomes 𝑓: 0.052 ( 2238 hom. )

Consequence

COL9A3
NM_001853.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.220

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=0.0029235482).

BP6

Variant 20-62827963-C-T is Benign according to our data. Variant chr20-62827963-C-T is described in ClinVar as Benign. ClinVar VariationId is 258436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A3	NM_001853.4 link	c.887C>T	p.Pro296Leu	missense_variant	Exon 17 of 32	ENST00000649368.1	NP_001844.3	Q14050

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A3	ENST00000649368.1 link	c.887C>T	p.Pro296Leu	missense_variant	Exon 17 of 32		NM_001853.4	ENSP00000496793.1		Q14050
COL9A3	ENST00000463487.2 link	n.595C>T		non_coding_transcript_exon_variant	Exon 9 of 11	5

Frequencies

GnomAD3 genomes

AF:

0.0399

AC:

6075

AN:

152152

Hom.:

197

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0119

Gnomad AMI

AF:

0.0910

Gnomad AMR

AF:

0.0445

Gnomad ASJ

AF:

0.0380

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00455

Gnomad FIN

AF:

0.0364

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0612

Gnomad OTH

AF:

0.0464

GnomAD2 exomes

AF:

0.0387

AC:

9686

AN:

250168

AF XY:

0.0388

show subpopulations

Gnomad AFR exome

AF:

0.00993

Gnomad AMR exome

AF:

0.0352

Gnomad ASJ exome

AF:

0.0392

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0373

Gnomad NFE exome

AF:

0.0585

Gnomad OTH exome

AF:

0.0501

GnomAD4 exome

AF:

0.0517

AC:

75547

AN:

1460590

Hom.:

2238

Cov.:

AF XY:

0.0507

AC XY:

36852

AN XY:

726612

show subpopulations

African (AFR)

AF:

0.00968

AC:

324

AN:

33478

American (AMR)

AF:

0.0364

AC:

1628

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0402

AC:

1050

AN:

26132

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.00720

AC:

621

AN:

86258

European-Finnish (FIN)

AF:

0.0363

AC:

1899

AN:

52274

Middle Eastern (MID)

AF:

0.0359

AC:

207

AN:

5768

European-Non Finnish (NFE)

AF:

0.0603

AC:

67076

AN:

1111888

Other (OTH)

AF:

0.0454

AC:

2739

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

4001

8001

12002

16002

20003

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2494

4988

7482

9976

12470

<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:

0.0399

AC:

6071

AN:

152270

Hom.:

197

Cov.:

AF XY:

0.0382

AC XY:

2842

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0119

AC:

495

AN:

41548

American (AMR)

AF:

0.0444

AC:

679

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0380

AC:

132

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00456

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0364

AC:

386

AN:

10612

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0612

AC:

4159

AN:

68012

Other (OTH)

AF:

0.0459

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

309

618

928

1237

1546

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0493

Hom.:

392

Bravo

AF:

0.0398

TwinsUK

AF:

0.0634

AC:

235

ALSPAC

AF:

0.0589

AC:

227

ESP6500AA

AF:

0.0136

AC:

ESP6500EA

AF:

0.0613

AC:

527

ExAC

AF:

0.0377

AC:

4569

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.0559

EpiControl

AF:

0.0643

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Aug 10, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

not specified

Benign:2

Sep 14, 2017

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Connective tissue disorder

Benign:1

Jun 03, 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

0.061

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.27

CADD

Benign

8.9

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.037

T;T

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.66

.;T

MetaRNN

Benign

0.0029

T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

0.70

N;N

PhyloP100

-0.22

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.6

.;D

REVEL

Benign

0.25

Sift

Benign

0.63

.;T

Sift4G

Uncertain

0.050

.;T

Polyphen

0.027

B;B

Vest4

0.062

MPC

0.079

ClinPred

0.016

GERP RS

1.1

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.1

Varity_R

0.11

gMVP

0.56

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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