rs1135056

Variant names:

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.1862A>G(p.Gln621Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 1,613,484 control chromosomes in the GnomAD database, including 128,924 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. Q621W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.38 ( 10978 hom., cov: 32)

Exomes 𝑓: 0.40 ( 117946 hom. )

Consequence

COL9A1
NM_001851.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.73

Publications

40 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=0.019637465).

BP6

Variant 6-70252130-T-C is Benign according to our data. Variant chr6-70252130-T-C is described in ClinVar as Benign. ClinVar VariationId is 258353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A1	NM_001851.6 link	c.1862A>G	p.Gln621Arg	missense_variant	Exon 28 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.1862A>G	p.Gln621Arg	missense_variant	Exon 28 of 38	1	NM_001851.6	ENSP00000349790.6

Frequencies

GnomAD3 genomes

AF:

0.378

AC:

57506

AN:

151940

Hom.:

10977

Cov.:

show subpopulations

Gnomad AFR

AF:

0.353

Gnomad AMI

AF:

0.360

Gnomad AMR

AF:

0.319

Gnomad ASJ

AF:

0.431

Gnomad EAS

AF:

0.284

Gnomad SAS

AF:

0.292

Gnomad FIN

AF:

0.394

Gnomad MID

AF:

0.421

Gnomad NFE

AF:

0.416

Gnomad OTH

AF:

0.369

GnomAD2 exomes

AF:

0.371

AC:

93235

AN:

251222

AF XY:

0.373

show subpopulations

Gnomad AFR exome

AF:

0.355

Gnomad AMR exome

AF:

0.293

Gnomad ASJ exome

AF:

0.435

Gnomad EAS exome

AF:

0.283

Gnomad FIN exome

AF:

0.386

Gnomad NFE exome

AF:

0.420

Gnomad OTH exome

AF:

0.391

GnomAD4 exome

AF:

0.399

AC:

583423

AN:

1461426

Hom.:

117946

Cov.:

AF XY:

0.397

AC XY:

288408

AN XY:

727044

show subpopulations

African (AFR)

AF:

0.353

AC:

11817

AN:

33474

American (AMR)

AF:

0.295

AC:

13205

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.430

AC:

11224

AN:

26130

East Asian (EAS)

AF:

0.271

AC:

10777

AN:

39696

South Asian (SAS)

AF:

0.308

AC:

26538

AN:

86254

European-Finnish (FIN)

AF:

0.394

AC:

21061

AN:

53410

Middle Eastern (MID)

AF:

0.401

AC:

2303

AN:

5746

European-Non Finnish (NFE)

AF:

0.416

AC:

462730

AN:

1111628

Other (OTH)

AF:

0.394

AC:

23768

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

20399

40799

61198

81598

101997

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14112

28224

42336

56448

70560

<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:

0.378

AC:

57536

AN:

152058

Hom.:

10978

Cov.:

AF XY:

0.375

AC XY:

27860

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.353

AC:

14645

AN:

41456

American (AMR)

AF:

0.319

AC:

4872

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.431

AC:

1493

AN:

3468

East Asian (EAS)

AF:

0.283

AC:

1459

AN:

5164

South Asian (SAS)

AF:

0.293

AC:

1408

AN:

4810

European-Finnish (FIN)

AF:

0.394

AC:

4166

AN:

10574

Middle Eastern (MID)

AF:

0.425

AC:

125

AN:

294

European-Non Finnish (NFE)

AF:

0.416

AC:

28263

AN:

67986

Other (OTH)

AF:

0.369

AC:

777

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1840

3680

5519

7359

9199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

568

1136

1704

2272

2840

<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.:

56282

Bravo

AF:

0.375

TwinsUK

AF:

0.403

AC:

1496

ALSPAC

AF:

0.401

AC:

1545

ESP6500AA

AF:

0.348

AC:

1533

ESP6500EA

AF:

0.414

AC:

3559

ExAC

AF:

0.375

AC:

45542

Asia WGS

AF:

0.294

AC:

1022

AN:

3478

EpiCase

AF:

0.413

EpiControl

AF:

0.419

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 30, 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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Epiphyseal dysplasia, multiple, 6

Benign:1

Jul 30, 2021

Genome-Nilou Lab

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

0.057

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.072

T;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.0026

LIST_S2

Benign

0.075

T;T

MetaRNN

Benign

0.020

T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

-0.10

N;.

PhyloP100

1.7

PrimateAI

Benign

0.39

PROVEAN

Benign

0.61

N;N

REVEL

Benign

0.28

Sift

Benign

1.0

T;T

Sift4G

Benign

0.70

T;T

Polyphen

0.0010

B;B

Vest4

0.019

MPC

0.077

ClinPred

0.0041

GERP RS

4.9

Varity_R

0.043

gMVP

0.066

Mutation Taster

=98/2

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