rs45476191

Variant names:

Variant summary

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

The NM_001853.4(COL9A3):c.520-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,599,674 control chromosomes in the GnomAD database, including 212 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0090 ( 12 hom., cov: 33)

Exomes 𝑓: 0.014 ( 200 hom. )

Consequence

COL9A3
NM_001853.4 splice_region, intron

Scores

Splicing: ADA: 0.0003695

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.647

Publications

5 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 (BayesDel_noAF=-0.62).

BP6

Variant 20-62824439-C-T is Benign according to our data. Variant chr20-62824439-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00905 (1378/152272) while in subpopulation SAS AF = 0.0263 (127/4828). AF 95% confidence interval is 0.0226. There are 12 homozygotes in GnomAd4. There are 620 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A3	NM_001853.4 link	c.520-6C>T		splice_region_variant, intron_variant	Intron 10 of 31	ENST00000649368.1	NP_001844.3	Q14050

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A3	ENST00000649368.1 link	c.520-6C>T		splice_region_variant, intron_variant	Intron 10 of 31		NM_001853.4	ENSP00000496793.1		Q14050

Frequencies

GnomAD3 genomes

AF:

0.00906

AC:

1379

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00249

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.0226

Gnomad SAS

AF:

0.0265

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0137

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.0111

AC:

2512

AN:

225928

AF XY:

0.0123

show subpopulations

Gnomad AFR exome

AF:

0.00115

Gnomad AMR exome

AF:

0.00279

Gnomad ASJ exome

AF:

0.00188

Gnomad EAS exome

AF:

0.0206

Gnomad FIN exome

AF:

0.00191

Gnomad NFE exome

AF:

0.0125

Gnomad OTH exome

AF:

0.00588

GnomAD4 exome

AF:

0.0139

AC:

20138

AN:

1447402

Hom.:

200

Cov.:

AF XY:

0.0143

AC XY:

10271

AN XY:

718848

show subpopulations

African (AFR)

AF:

0.00180

AC:

AN:

33264

American (AMR)

AF:

0.00283

AC:

121

AN:

42830

Ashkenazi Jewish (ASJ)

AF:

0.00286

AC:

AN:

25854

East Asian (EAS)

AF:

0.0188

AC:

736

AN:

39046

South Asian (SAS)

AF:

0.0253

AC:

2133

AN:

84146

European-Finnish (FIN)

AF:

0.00301

AC:

154

AN:

51098

Middle Eastern (MID)

AF:

0.0131

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.0146

AC:

16130

AN:

1105654

Other (OTH)

AF:

0.0110

AC:

655

AN:

59802

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

1103

2206

3308

4411

5514

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

640

1280

1920

2560

3200

<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:

0.00905

AC:

1378

AN:

152272

Hom.:

Cov.:

AF XY:

0.00833

AC XY:

620

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00248

AC:

103

AN:

41556

American (AMR)

AF:

0.00301

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3470

East Asian (EAS)

AF:

0.0228

AC:

118

AN:

5172

South Asian (SAS)

AF:

0.0263

AC:

127

AN:

4828

European-Finnish (FIN)

AF:

0.00226

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0137

AC:

931

AN:

68000

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

156

235

313

391

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0101

Hom.:

Bravo

AF:

0.00815

Asia WGS

AF:

0.0250

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Sep 30, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 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

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:3

Aug 06, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Intervertebral disc disorder;C1832998:Epiphyseal dysplasia, multiple, 3

Benign:1

Aug 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Connective tissue disorder

Benign:1

Mar 11, 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

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

-0.65

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00037

dbscSNV1_RF

Benign

0.022

SpliceAI score (max)

0.19

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