rs592121

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_001851.6(COL9A1):c.1015T>C(p.Ser339Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,608,134 control chromosomes in the GnomAD database, including 130,770 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S339S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.46 ( 17851 hom., cov: 32)

Exomes 𝑓: 0.39 ( 112919 hom. )

Consequence

COL9A1
NM_001851.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.51

Publications

48 publications found

Variant links:

Genes affected

COL9A1 (HGNC:2217): (collagen type IX alpha 1 chain) This gene encodes one of the three alpha chains of type IX collagen, which is a minor (5-20%) collagen component of hyaline cartilage. Type IX collagen is usually found in tissues containing type II collagen, a fibrillar collagen. Studies in knockout mice have shown that synthesis of the alpha 1 chain is essential for assembly of type IX collagen molecules, a heterotrimeric molecule, and that lack of type IX collagen is associated with early onset osteoarthritis. Mutations in this gene are associated with osteoarthritis in humans, with multiple epiphyseal dysplasia, 6, a form of chondrodysplasia, and with Stickler syndrome, a disease characterized by ophthalmic, orofacial, articular, and auditory defects. Two transcript variants that encode different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

COL9A1 Gene-Disease associations (from GenCC):

epiphyseal dysplasia, multiple, 6
Inheritance: AD, AR, Unknown Classification: DEFINITIVE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Stickler syndrome, type 4
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, 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
Stickler syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

COL9A1 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=3.3340893E-6).

BP6

Variant 6-70274733-A-G is Benign according to our data. Variant chr6-70274733-A-G is described in ClinVar as Benign. ClinVar VariationId is 258335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A1	NM_001851.6 link	c.1015T>C	p.Ser339Pro	missense_variant	Exon 11 of 38	ENST00000357250.11	NP_001842.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A1	ENST00000357250.11 link	c.1015T>C	p.Ser339Pro	missense_variant	Exon 11 of 38	1	NM_001851.6	ENSP00000349790.6

Frequencies

GnomAD3 genomes

AF:

0.464

AC:

70492

AN:

151840

Hom.:

17804

Cov.:

show subpopulations

Gnomad AFR

AF:

0.677

Gnomad AMI

AF:

0.259

Gnomad AMR

AF:

0.418

Gnomad ASJ

AF:

0.352

Gnomad EAS

AF:

0.339

Gnomad SAS

AF:

0.461

Gnomad FIN

AF:

0.322

Gnomad MID

AF:

0.459

Gnomad NFE

AF:

0.387

Gnomad OTH

AF:

0.438

GnomAD2 exomes

AF:

0.395

AC:

99156

AN:

250848

AF XY:

0.395

show subpopulations

Gnomad AFR exome

AF:

0.687

Gnomad AMR exome

AF:

0.322

Gnomad ASJ exome

AF:

0.346

Gnomad EAS exome

AF:

0.343

Gnomad FIN exome

AF:

0.321

Gnomad NFE exome

AF:

0.387

Gnomad OTH exome

AF:

0.389

GnomAD4 exome

AF:

0.389

AC:

566143

AN:

1456174

Hom.:

112919

Cov.:

AF XY:

0.390

AC XY:

282842

AN XY:

724768

show subpopulations

African (AFR)

AF:

0.693

AC:

23100

AN:

33322

American (AMR)

AF:

0.332

AC:

14852

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.348

AC:

9082

AN:

26076

East Asian (EAS)

AF:

0.370

AC:

14677

AN:

39658

South Asian (SAS)

AF:

0.451

AC:

38837

AN:

86124

European-Finnish (FIN)

AF:

0.329

AC:

17547

AN:

53254

Middle Eastern (MID)

AF:

0.452

AC:

2602

AN:

5758

European-Non Finnish (NFE)

AF:

0.381

AC:

421649

AN:

1107116

Other (OTH)

AF:

0.395

AC:

23797

AN:

60174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

17062

34125

51187

68250

85312

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13316

26632

39948

53264

66580

<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:

0.465

AC:

70592

AN:

151960

Hom.:

17851

Cov.:

AF XY:

0.461

AC XY:

34237

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.677

AC:

28060

AN:

41442

American (AMR)

AF:

0.418

AC:

6369

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.352

AC:

1222

AN:

3470

East Asian (EAS)

AF:

0.338

AC:

1746

AN:

5168

South Asian (SAS)

AF:

0.462

AC:

2223

AN:

4812

European-Finnish (FIN)

AF:

0.322

AC:

3399

AN:

10566

Middle Eastern (MID)

AF:

0.459

AC:

135

AN:

294

European-Non Finnish (NFE)

AF:

0.387

AC:

26273

AN:

67952

Other (OTH)

AF:

0.442

AC:

929

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1830

3660

5489

7319

9149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

626

1252

1878

2504

3130

<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:

0.405

Hom.:

62391

Bravo

AF:

0.475

TwinsUK

AF:

0.381

AC:

1413

ALSPAC

AF:

0.372

AC:

1433

ESP6500AA

AF:

0.679

AC:

2993

ESP6500EA

AF:

0.378

AC:

3247

ExAC

AF:

0.406

AC:

49336

Asia WGS

AF:

0.413

AC:

1438

AN:

3478

EpiCase

AF:

0.389

EpiControl

AF:

0.385

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

Sep 29, 2016

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. -

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

- -

Epiphyseal dysplasia, multiple, 6

Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

0.048

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

T;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.39

T;T

MetaRNN

Benign

0.0000033

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-1.4

N;.

PhyloP100

2.5

PrimateAI

Uncertain

0.53

PROVEAN

Benign

2.9

N;N

REVEL

Uncertain

0.38

Sift

Benign

1.0

T;T

Sift4G

Benign

0.94

T;T

Polyphen

0.0010

B;B

Vest4

0.052

MPC

0.087

ClinPred

0.0068

GERP RS

5.0

Varity_R

0.15

gMVP

0.18

Mutation Taster

=94/6

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