20-62821797-T-C

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.410T>C(p.Leu137Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00396 in 1,605,626 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L137F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0039 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0040 ( 28 hom. )

Consequence

COL9A3
NM_001853.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.79

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=0.009360015).

BP6

Variant 20-62821797-T-C is Benign according to our data. Variant chr20-62821797-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258424.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 = 0.0039 (593/152218) while in subpopulation SAS AF = 0.00518 (25/4824). AF 95% confidence interval is 0.00418. There are 4 homozygotes in GnomAd4. There are 272 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A3	NM_001853.4 link	c.410T>C	p.Leu137Pro	missense_variant	Exon 8 of 32	ENST00000649368.1	NP_001844.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
COL9A3	ENST00000649368.1 link	c.410T>C	p.Leu137Pro	missense_variant	Exon 8 of 32		NM_001853.4	ENSP00000496793.1
COL9A3	ENST00000452372.2 link	c.299T>C	p.Leu100Pro	missense_variant	Exon 7 of 12	5		ENSP00000394280.1
COL9A3	ENST00000477612.5 link	n.406T>C		non_coding_transcript_exon_variant	Exon 8 of 12	3
COL9A3	ENST00000489045.5 link	n.456T>C		non_coding_transcript_exon_variant	Exon 7 of 14	5

Frequencies

GnomAD3 genomes

AF:

0.00391

AC:

594

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00360

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00150

Gnomad ASJ

AF:

0.0210

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00462

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00386

AC:

934

AN:

241728

AF XY:

0.00404

show subpopulations

Gnomad AFR exome

AF:

0.00386

Gnomad AMR exome

AF:

0.00187

Gnomad ASJ exome

AF:

0.0167

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000435

Gnomad NFE exome

AF:

0.00407

Gnomad OTH exome

AF:

0.00614

GnomAD4 exome

AF:

0.00397

AC:

5771

AN:

1453408

Hom.:

Cov.:

AF XY:

0.00401

AC XY:

2900

AN XY:

722990

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00300

AC:

100

AN:

33368

American (AMR)

AF:

0.00206

AC:

AN:

44562

Ashkenazi Jewish (ASJ)

AF:

0.0170

AC:

442

AN:

26014

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.00565

AC:

484

AN:

85636

European-Finnish (FIN)

AF:

0.000695

AC:

AN:

51794

Middle Eastern (MID)

AF:

0.00551

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.00392

AC:

4337

AN:

1106734

Other (OTH)

AF:

0.00415

AC:

249

AN:

60036

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.386

Heterozygous variant carriers

241

482

723

964

1205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

328

492

656

820

<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:

0.00390

AC:

593

AN:

152218

Hom.:

Cov.:

AF XY:

0.00365

AC XY:

272

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00359

AC:

149

AN:

41530

American (AMR)

AF:

0.00150

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0210

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5160

South Asian (SAS)

AF:

0.00518

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00460

AC:

313

AN:

67988

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00485

Hom.:

Bravo

AF:

0.00393

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.00315

AC:

ExAC

AF:

0.00382

AC:

461

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

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

Nov 13, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL9A3: BS2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely 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

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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

Oct 22, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Connective tissue disorder

Benign:1

Aug 19, 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

0.099

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.00037

T;T;.

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.0

.;T;T

M_CAP

Benign

0.067

MetaRNN

Benign

0.0094

T;T;T

MetaSVM

Benign

-0.41

MutationAssessor

Benign

-1.2

N;N;.

PhyloP100

1.8

PrimateAI

Uncertain

0.68

PROVEAN

Benign

0.0

.;N;N

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;T;T

Sift4G

Pathogenic

0.0

.;T;T

Vest4

0.0

ClinPred

0.0086

GERP RS

4.8

Varity_R

0.13

gMVP

0.50

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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