rs9346373

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001851.6(COL9A1):c.1728T>G(p.Pro576Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,602,762 control chromosomes in the GnomAD database, including 12,555 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P576P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.15 ( 2330 hom., cov: 32)

Exomes 𝑓: 0.11 ( 10225 hom. )

Consequence

COL9A1
NM_001851.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.812

Publications

12 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 6-70253421-A-C is Benign according to our data. Variant chr6-70253421-A-C is described in ClinVar as Benign. ClinVar VariationId is 195957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.812 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A1	NM_001851.6 link	c.1728T>G	p.Pro576Pro	synonymous_variant	Exon 26 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.1728T>G	p.Pro576Pro	synonymous_variant	Exon 26 of 38	1	NM_001851.6	ENSP00000349790.6		P20849-1

Frequencies

GnomAD3 genomes

AF:

0.155

AC:

23534

AN:

152106

Hom.:

2324

Cov.:

show subpopulations

Gnomad AFR

AF:

0.273

Gnomad AMI

AF:

0.104

Gnomad AMR

AF:

0.154

Gnomad ASJ

AF:

0.135

Gnomad EAS

AF:

0.0842

Gnomad SAS

AF:

0.203

Gnomad FIN

AF:

0.0530

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.157

GnomAD2 exomes

AF:

0.125

AC:

31423

AN:

251226

AF XY:

0.125

show subpopulations

Gnomad AFR exome

AF:

0.277

Gnomad AMR exome

AF:

0.126

Gnomad ASJ exome

AF:

0.138

Gnomad EAS exome

AF:

0.0825

Gnomad FIN exome

AF:

0.0470

Gnomad NFE exome

AF:

0.103

Gnomad OTH exome

AF:

0.129

GnomAD4 exome

AF:

0.111

AC:

161528

AN:

1450540

Hom.:

10225

Cov.:

AF XY:

0.114

AC XY:

82384

AN XY:

722234

show subpopulations

African (AFR)

AF:

0.281

AC:

9301

AN:

33158

American (AMR)

AF:

0.131

AC:

5859

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.137

AC:

3576

AN:

26012

East Asian (EAS)

AF:

0.127

AC:

5038

AN:

39612

South Asian (SAS)

AF:

0.195

AC:

16689

AN:

85590

European-Finnish (FIN)

AF:

0.0482

AC:

2569

AN:

53282

Middle Eastern (MID)

AF:

0.178

AC:

1023

AN:

5738

European-Non Finnish (NFE)

AF:

0.0998

AC:

110026

AN:

1102532

Other (OTH)

AF:

0.124

AC:

7447

AN:

59940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

5939

11878

17817

23756

29695

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4158

8316

12474

16632

20790

<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:

0.155

AC:

23566

AN:

152222

Hom.:

2330

Cov.:

AF XY:

0.152

AC XY:

11281

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.273

AC:

11331

AN:

41492

American (AMR)

AF:

0.154

AC:

2357

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

468

AN:

3468

East Asian (EAS)

AF:

0.0846

AC:

439

AN:

5190

South Asian (SAS)

AF:

0.203

AC:

979

AN:

4818

European-Finnish (FIN)

AF:

0.0530

AC:

563

AN:

10620

Middle Eastern (MID)

AF:

0.190

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.102

AC:

6942

AN:

68014

Other (OTH)

AF:

0.159

AC:

336

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

963

1925

2888

3850

4813

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

244

488

732

976

1220

<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:

0.119

Hom.:

1984

Bravo

AF:

0.164

Asia WGS

AF:

0.156

AC:

544

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2015

Eurofins Ntd Llc (ga)

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. -

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

BayesDel_noAF

Benign

-0.54

CADD

Benign

9.5

(source)

DANN

Benign

0.74

PhyloP100

0.81

Mutation Taster

=100/0

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