rs77706858

Variant names:

Variant summary

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

The NM_001851.6(COL9A1):c.1349A>G(p.Glu450Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00402 in 1,609,246 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0041 ( 13 hom. )

Consequence

COL9A1
NM_001851.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 6.01

Publications

14 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=0.015095472).

BP6

Variant 6-70263290-T-C is Benign according to our data. Variant chr6-70263290-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00336 (512/152180) while in subpopulation NFE AF = 0.00496 (337/67964). AF 95% confidence interval is 0.00452. There are 0 homozygotes in GnomAd4. There are 251 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 13 AR,AD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A1	NM_001851.6 link	c.1349A>G	p.Glu450Gly	missense_variant	Exon 19 of 38	ENST00000357250.11	NP_001842.3	P20849-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A1	ENST00000357250.11 link	c.1349A>G	p.Glu450Gly	missense_variant	Exon 19 of 38	1	NM_001851.6	ENSP00000349790.6		P20849-1

Frequencies

GnomAD3 genomes

AF:

0.00336

AC:

511

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00197

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00821

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00494

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00364

AC:

907

AN:

249288

AF XY:

0.00363

show subpopulations

Gnomad AFR exome

AF:

0.000873

Gnomad AMR exome

AF:

0.000901

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00732

Gnomad NFE exome

AF:

0.00573

Gnomad OTH exome

AF:

0.00427

GnomAD4 exome

AF:

0.00409

AC:

5956

AN:

1457066

Hom.:

Cov.:

AF XY:

0.00402

AC XY:

2910

AN XY:

724594

show subpopulations

African (AFR)

AF:

0.000750

AC:

AN:

33348

American (AMR)

AF:

0.00134

AC:

AN:

44616

Ashkenazi Jewish (ASJ)

AF:

0.00215

AC:

AN:

26044

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39548

South Asian (SAS)

AF:

0.000624

AC:

AN:

84882

European-Finnish (FIN)

AF:

0.00892

AC:

474

AN:

53168

Middle Eastern (MID)

AF:

0.000869

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00456

AC:

5065

AN:

1109568

Other (OTH)

AF:

0.00361

AC:

217

AN:

60138

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

267

535

802

1070

1337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

174

348

522

696

870

<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:

0.00336

AC:

512

AN:

152180

Hom.:

Cov.:

AF XY:

0.00337

AC XY:

251

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.000915

AC:

AN:

41546

American (AMR)

AF:

0.00196

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00821

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00496

AC:

337

AN:

67964

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00456

Hom.:

Bravo

AF:

0.00291

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00442

AC:

536

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Jun 07, 2019

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL9A1: BS2 -

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

- -

Dec 18, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26770814, 24828792, 27353947) -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 15, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Epiphyseal dysplasia, multiple, 6

Benign:1

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Connective tissue disorder

Benign:1

Mar 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

D;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.015

T;T

MetaSVM

Uncertain

-0.011

MutationAssessor

Benign

0.69

N;.

PhyloP100

6.0

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-4.0

D;D

REVEL

Uncertain

0.54

Sift

Benign

0.046

D;D

Sift4G

Benign

0.19

T;T

Polyphen

1.0

D;D

Vest4

0.65

MVP

0.92

MPC

0.45

ClinPred

0.017

GERP RS

5.5

Varity_R

0.45

gMVP

0.47

Mutation Taster

=96/4

polymorphism

(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