20-62817581-C-A

Variant summary

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

The NM_001853.4(COL9A3):​c.93C>A​(p.Pro31Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0811 in 1,539,566 control chromosomes in the GnomAD database, including 6,673 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1252 hom., cov: 33)
Exomes 𝑓: 0.077 ( 5421 hom. )

Consequence

COL9A3
NM_001853.4 synonymous

Scores

2

Clinical Significance

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

Conservation

PhyloP100: 0.0150

Publications

11 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

Genome browser will be placed here

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=-0.66).
BP6
Variant 20-62817581-C-A is Benign according to our data. Variant chr20-62817581-C-A is described in CliVar as Benign. Clinvar id is 195154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-62817581-C-A is described in CliVar as Benign. Clinvar id is 195154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-62817581-C-A is described in CliVar as Benign. Clinvar id is 195154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-62817581-C-A is described in CliVar as Benign. Clinvar id is 195154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-62817581-C-A is described in CliVar as Benign. Clinvar id is 195154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.015 with no splicing effect.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL9A3NM_001853.4 linkc.93C>A p.Pro31Pro synonymous_variant Exon 2 of 32 ENST00000649368.1 NP_001844.3 Q14050

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL9A3ENST00000649368.1 linkc.93C>A p.Pro31Pro synonymous_variant Exon 2 of 32 NM_001853.4 ENSP00000496793.1 Q14050
COL9A3ENST00000477612.5 linkn.89C>A non_coding_transcript_exon_variant Exon 2 of 12 3
COL9A3ENST00000489045.5 linkn.139C>A non_coding_transcript_exon_variant Exon 1 of 14 5
COL9A3ENST00000452372.2 linkc.-253C>A upstream_gene_variant 5 ENSP00000394280.1 Q4VXW1

Frequencies

GnomAD3 genomes
AF:
0.116
AC:
17559
AN:
151698
Hom.:
1248
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.182
Gnomad AMI
AF:
0.0735
Gnomad AMR
AF:
0.131
Gnomad ASJ
AF:
0.107
Gnomad EAS
AF:
0.272
Gnomad SAS
AF:
0.0940
Gnomad FIN
AF:
0.0895
Gnomad MID
AF:
0.111
Gnomad NFE
AF:
0.0664
Gnomad OTH
AF:
0.130
GnomAD2 exomes
AF:
0.110
AC:
15857
AN:
143678
AF XY:
0.106
show subpopulations
Gnomad AFR exome
AF:
0.191
Gnomad AMR exome
AF:
0.140
Gnomad ASJ exome
AF:
0.113
Gnomad EAS exome
AF:
0.282
Gnomad FIN exome
AF:
0.0843
Gnomad NFE exome
AF:
0.0683
Gnomad OTH exome
AF:
0.100
GnomAD4 exome
AF:
0.0773
AC:
107298
AN:
1387750
Hom.:
5421
Cov.:
30
AF XY:
0.0774
AC XY:
52982
AN XY:
684142
show subpopulations
African (AFR)
AF:
0.184
AC:
5776
AN:
31450
American (AMR)
AF:
0.137
AC:
4853
AN:
35550
Ashkenazi Jewish (ASJ)
AF:
0.112
AC:
2817
AN:
25098
East Asian (EAS)
AF:
0.270
AC:
9624
AN:
35608
South Asian (SAS)
AF:
0.0900
AC:
6947
AN:
77218
European-Finnish (FIN)
AF:
0.0810
AC:
3858
AN:
47632
Middle Eastern (MID)
AF:
0.118
AC:
637
AN:
5392
European-Non Finnish (NFE)
AF:
0.0628
AC:
67308
AN:
1072226
Other (OTH)
AF:
0.0951
AC:
5478
AN:
57576
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.488
Heterozygous variant carriers
0
4460
8920
13380
17840
22300
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2668
5336
8004
10672
13340
<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:
0.116
AC:
17601
AN:
151816
Hom.:
1252
Cov.:
33
AF XY:
0.117
AC XY:
8709
AN XY:
74184
show subpopulations
African (AFR)
AF:
0.182
AC:
7547
AN:
41522
American (AMR)
AF:
0.132
AC:
2013
AN:
15254
Ashkenazi Jewish (ASJ)
AF:
0.107
AC:
370
AN:
3466
East Asian (EAS)
AF:
0.272
AC:
1400
AN:
5148
South Asian (SAS)
AF:
0.0941
AC:
439
AN:
4666
European-Finnish (FIN)
AF:
0.0895
AC:
950
AN:
10618
Middle Eastern (MID)
AF:
0.116
AC:
34
AN:
294
European-Non Finnish (NFE)
AF:
0.0664
AC:
4506
AN:
67830
Other (OTH)
AF:
0.131
AC:
275
AN:
2106
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.499
Heterozygous variant carriers
0
797
1593
2390
3186
3983
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
196
392
588
784
980
<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:
0.0787
Hom.:
315
Bravo
AF:
0.125

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Jun 15, 2017
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. -

-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Oct 30, 2015
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:3
Nov 29, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
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

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Epiphyseal dysplasia, multiple, 3 Benign:1
Jul 30, 2021
Genome-Nilou Lab
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
-0.66
CADD
Benign
2.9
DANN
Benign
0.77
PhyloP100
0.015
PromoterAI
-0.0034
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Mutation Taster
=100/0
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs2273078; hg19: chr20-61448933; COSMIC: COSV51699160; COSMIC: COSV51699160; API