rs139573483

Positions:

chr20-62826783-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001853.4(COL9A3):c.755G>A(p.Arg252Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00303 in 1,612,796 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 8 hom. )

Consequence

COL9A3
NM_001853.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.53

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 links:

COL9A3 (HGNC:):

COL9A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015597671).

BP6

Variant 20-62826783-G-A is Benign according to our data. Variant chr20-62826783-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 258432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-62826783-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0023 (350/152278) while in subpopulation NFE AF= 0.004 (272/67990). AF 95% confidence interval is 0.00361. There are 2 homozygotes in gnomad4. There are 174 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL9A3	NM_001853.4 linkuse as main transcript	c.755G>A	p.Arg252Gln	missense_variant	15/32	ENST00000649368.1	NP_001844.3	Q14050

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL9A3	ENST00000649368.1 linkuse as main transcript	c.755G>A	p.Arg252Gln	missense_variant	15/32		NM_001853.4	ENSP00000496793.1	Q14050
COL9A3	ENST00000463487.2 linkuse as main transcript	n.463G>A		non_coding_transcript_exon_variant	7/11	5
COL9A3	ENST00000489045.5 linkuse as main transcript	n.801G>A		non_coding_transcript_exon_variant	14/14	5

Frequencies

GnomAD3 genomes

AF:

0.00230

AC:

350

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00400

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00217

AC:

541

AN:

248894

Hom.:

AF XY:

0.00223

AC XY:

301

AN XY:

135192

show subpopulations

Gnomad AFR exome

AF:

0.000188

Gnomad AMR exome

AF:

0.000667

Gnomad ASJ exome

AF:

0.00130

Gnomad EAS exome

AF:

0.000327

Gnomad SAS exome

AF:

0.00134

Gnomad FIN exome

AF:

0.00300

Gnomad NFE exome

AF:

0.00338

Gnomad OTH exome

AF:

0.00198

GnomAD4 exome

AF:

0.00311

AC:

4537

AN:

1460518

Hom.:

Cov.:

AF XY:

0.00300

AC XY:

2183

AN XY:

726568

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.00149

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00151

Gnomad4 FIN exome

AF:

0.00284

Gnomad4 NFE exome

AF:

0.00361

Gnomad4 OTH exome

AF:

0.00278

GnomAD4 genome

AF:

0.00230

AC:

350

AN:

152278

Hom.:

Cov.:

AF XY:

0.00234

AC XY:

174

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00292

Gnomad4 NFE

AF:

0.00400

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00295

Hom.:

Bravo

AF:

0.00209

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00384

AC:

ExAC

AF:

0.00225

AC:

272

EpiCase

AF:

0.00300

EpiControl

AF:

0.00320

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 23, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	COL9A3: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 21, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 22, 2017	- -

Connective tissue disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.00064

T;T

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.74

.;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.016

T;T

MetaSVM

Benign

-0.41

MutationAssessor

Benign

0.71

N;N

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.62

.;N

REVEL

Uncertain

0.33

Sift

Uncertain

0.0060

.;D

Sift4G

Benign

0.52

.;T

Polyphen

0.0030

B;B

Vest4

0.36

MVP

0.69

MPC

0.081

ClinPred

0.019

GERP RS

3.8

Varity_R

0.13

gMVP

0.55

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over