Genetic Variant COL9A3:p.Arg682Gly (chr20-62840721-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001853.4(COL9A3):c.2044C>G(p.Arg682Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,419,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R682S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

COL9A3
NM_001853.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.811

Publications

15 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22288772).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A3	NM_001853.4 link	c.2044C>G	p.Arg682Gly	missense_variant	Exon 32 of 32	ENST00000649368.1	NP_001844.3	Q14050
COL9A3	XM_047439893.1 link	c.2221C>G	p.Arg741Gly	missense_variant	Exon 31 of 31		XP_047295849.1
COL9A3	XM_047439894.1 link	c.1483C>G	p.Arg495Gly	missense_variant	Exon 32 of 32		XP_047295850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A3	ENST00000649368.1 link	c.2044C>G	p.Arg682Gly	missense_variant	Exon 32 of 32		NM_001853.4	ENSP00000496793.1		Q14050

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000558

AC:

AN:

179196

AF XY:

0.0000105

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000141

AC:

AN:

1419722

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

702156

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32754

American (AMR)

AF:

0.00

AC:

AN:

37608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25378

East Asian (EAS)

AF:

0.00

AC:

AN:

37648

South Asian (SAS)

AF:

0.0000246

AC:

AN:

81272

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50686

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1089836

Other (OTH)

AF:

0.00

AC:

AN:

58822

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000855

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.033

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.00044

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.69

.;T

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-0.33

MutationAssessor

Benign

0.41

N;N

PhyloP100

0.81

PrimateAI

Benign

0.40

PROVEAN

Benign

2.2

.;N

REVEL

Uncertain

0.40

Sift

Uncertain

0.0060

.;D

Sift4G

Benign

0.18

.;T

Polyphen

0.72

P;P

Vest4

0.35

MutPred

0.41

Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);

MVP

0.57

MPC

0.38

ClinPred

0.43

GERP RS

0.95

Varity_R

0.16

gMVP

0.67

Mutation Taster

=89/11

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over