rs751557

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001853.4(COL9A3):c.1304C>A(p.Ala435Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,605,876 control chromosomes in the GnomAD database, including 35,943 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 5433 hom., cov: 34)

Exomes 𝑓: 0.20 ( 30510 hom. )

Consequence

COL9A3
NM_001853.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.552

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=0.012107581).

BP6

Variant 20-62832170-C-A is Benign according to our data. Variant chr20-62832170-C-A is described in ClinVar as [Benign]. Clinvar id is 195873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-62832170-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL9A3	NM_001853.4 linkuse as main transcript	c.1304C>A	p.Ala435Glu	missense_variant	25/32	ENST00000649368.1	NP_001844.3	Q14050

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL9A3	ENST00000649368.1 linkuse as main transcript	c.1304C>A	p.Ala435Glu	missense_variant	25/32		NM_001853.4	ENSP00000496793.1		Q14050

Frequencies

GnomAD3 genomes

AF:

0.245

AC:

37221

AN:

152156

Hom.:

5424

Cov.:

show subpopulations

Gnomad AFR

AF:

0.407

Gnomad AMI

AF:

0.0943

Gnomad AMR

AF:

0.158

Gnomad ASJ

AF:

0.158

Gnomad EAS

AF:

0.0592

Gnomad SAS

AF:

0.107

Gnomad FIN

AF:

0.205

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.203

Gnomad OTH

AF:

0.225

GnomAD3 exomes

AF:

0.175

AC:

43549

AN:

249060

Hom.:

4746

AF XY:

0.172

AC XY:

23167

AN XY:

134996

show subpopulations

Gnomad AFR exome

AF:

0.411

Gnomad AMR exome

AF:

0.0981

Gnomad ASJ exome

AF:

0.147

Gnomad EAS exome

AF:

0.0564

Gnomad SAS exome

AF:

0.103

Gnomad FIN exome

AF:

0.207

Gnomad NFE exome

AF:

0.200

Gnomad OTH exome

AF:

0.182

GnomAD4 exome

AF:

0.195

AC:

283521

AN:

1453602

Hom.:

30510

Cov.:

AF XY:

0.192

AC XY:

138993

AN XY:

723428

show subpopulations

Gnomad4 AFR exome

AF:

0.423

Gnomad4 AMR exome

AF:

0.105

Gnomad4 ASJ exome

AF:

0.154

Gnomad4 EAS exome

AF:

0.0491

Gnomad4 SAS exome

AF:

0.104

Gnomad4 FIN exome

AF:

0.202

Gnomad4 NFE exome

AF:

0.205

Gnomad4 OTH exome

AF:

0.189

GnomAD4 genome

AF:

0.245

AC:

37268

AN:

152274

Hom.:

5433

Cov.:

AF XY:

0.238

AC XY:

17703

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.407

Gnomad4 AMR

AF:

0.158

Gnomad4 ASJ

AF:

0.158

Gnomad4 EAS

AF:

0.0591

Gnomad4 SAS

AF:

0.107

Gnomad4 FIN

AF:

0.205

Gnomad4 NFE

AF:

0.203

Gnomad4 OTH

AF:

0.222

Alfa

AF:

0.204

Hom.:

4782

Bravo

AF:

0.250

TwinsUK

AF:

0.221

AC:

820

ALSPAC

AF:

0.208

AC:

800

ESP6500AA

AF:

0.397

AC:

1747

ESP6500EA

AF:

0.206

AC:

1774

ExAC

AF:

0.182

AC:

22049

Asia WGS

AF:

0.100

AC:

350

AN:

3478

EpiCase

AF:

0.193

EpiControl

AF:

0.200

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 21, 2015	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2018	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. -

Epiphyseal dysplasia, multiple, 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.00099

T;T

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.69

.;T

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.64

N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.63

.;N

REVEL

Benign

0.23

Sift

Benign

0.37

.;T

Sift4G

Benign

0.58

.;T

Polyphen

0.081

B;B

Vest4

0.11

MPC

0.40

ClinPred

0.013

GERP RS

4.2

Varity_R

0.091

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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