rs142792529

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_StrongBS1BS2

The NM_001853.4(COL9A3):c.1816G>A(p.Ala606Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,552,770 control chromosomes in the GnomAD database, including 148 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. A606S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0090 ( 5 hom., cov: 32)

Exomes 𝑓: 0.012 ( 143 hom. )

Consequence

COL9A3
NM_001853.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.836

Publications

8 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 (MetaRNN=0.0031912327).

BP6

Variant 20-62838713-G-A is Benign according to our data. Variant chr20-62838713-G-A is described in ClinVar as Benign. ClinVar VariationId is 258418.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 = 0.00898 (1367/152300) while in subpopulation NFE AF = 0.0141 (959/68028). AF 95% confidence interval is 0.0134. There are 5 homozygotes in GnomAd4. There are 661 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COL9A3	NM_001853.4 link	c.1816G>A	p.Ala606Thr	missense_variant	Exon 31 of 32	ENST00000649368.1	NP_001844.3
COL9A3	XM_047439893.1 link	c.1993G>A	p.Ala665Thr	missense_variant	Exon 30 of 31		XP_047295849.1
COL9A3	XM_047439894.1 link	c.1255G>A	p.Ala419Thr	missense_variant	Exon 31 of 32		XP_047295850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A3	ENST00000649368.1 link	c.1816G>A	p.Ala606Thr	missense_variant	Exon 31 of 32		NM_001853.4	ENSP00000496793.1

Frequencies

GnomAD3 genomes

AF:

0.00900

AC:

1370

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00347

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00829

Gnomad FIN

AF:

0.0169

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0141

Gnomad OTH

AF:

0.00479

GnomAD2 exomes

AF:

0.00869

AC:

1374

AN:

158024

AF XY:

0.00892

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.00233

Gnomad ASJ exome

AF:

0.00515

Gnomad EAS exome

AF:

0.000348

Gnomad FIN exome

AF:

0.0168

Gnomad NFE exome

AF:

0.0128

Gnomad OTH exome

AF:

0.00495

GnomAD4 exome

AF:

0.0125

AC:

17451

AN:

1400470

Hom.:

143

Cov.:

AF XY:

0.0123

AC XY:

8476

AN XY:

690850

show subpopulations

African (AFR)

AF:

0.00190

AC:

AN:

31652

American (AMR)

AF:

0.00265

AC:

AN:

35822

Ashkenazi Jewish (ASJ)

AF:

0.00445

AC:

112

AN:

25188

East Asian (EAS)

AF:

0.000390

AC:

AN:

35874

South Asian (SAS)

AF:

0.00816

AC:

647

AN:

79272

European-Finnish (FIN)

AF:

0.0169

AC:

835

AN:

49358

Middle Eastern (MID)

AF:

0.00527

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0140

AC:

15118

AN:

1079532

Other (OTH)

AF:

0.00930

AC:

540

AN:

58074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

962

1924

2886

3848

4810

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

566

1132

1698

2264

2830

<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:

0.00898

AC:

1367

AN:

152300

Hom.:

Cov.:

AF XY:

0.00888

AC XY:

661

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00262

AC:

109

AN:

41556

American (AMR)

AF:

0.00346

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3472

East Asian (EAS)

AF:

0.000578

AC:

AN:

5190

South Asian (SAS)

AF:

0.00809

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0169

AC:

179

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0141

AC:

959

AN:

68028

Other (OTH)

AF:

0.00474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

135

202

270

337

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:

0.0114

Hom.:

Bravo

AF:

0.00754

TwinsUK

AF:

0.0121

AC:

ALSPAC

AF:

0.0143

AC:

ESP6500AA

AF:

0.00374

AC:

ESP6500EA

AF:

0.0123

AC:

103

ExAC

AF:

0.00533

AC:

526

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Feb 03, 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

- -

Sep 30, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 27, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL9A3: BP4, BS1, BS2 -

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:2

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

- -

Connective tissue disorder

Benign:1

May 21, 2021

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

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

3.2

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.42

.;T

MetaRNN

Benign

0.0032

T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

1.6

L;L

PhyloP100

-0.84

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.72

.;N

REVEL

Benign

0.18

Sift

Benign

0.57

.;T

Sift4G

Benign

0.53

.;T

Polyphen

0.20

B;B

Vest4

0.21

MVP

0.53

MPC

0.30

ClinPred

0.0057

GERP RS

-0.78

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.016

gMVP

0.35

Mutation Taster

=98/2

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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