20-62819981-G-A

Position:

chr20-62819981-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBS1BS2

The NM_001853.4(COL9A3):c.308G>A(p.Arg103Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,612,462 control chromosomes in the GnomAD database, including 279 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R103W) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0096 ( 16 hom., cov: 33)

Exomes 𝑓: 0.015 ( 263 hom. )

Consequence

COL9A3
NM_001853.4 missense, splice_region

Scores

Splicing: ADA: 0.004469

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.98

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-62819980-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.0064404905).

BP6

Variant 20-62819981-G-A is Benign according to our data. Variant chr20-62819981-G-A is described in ClinVar as [Benign]. Clinvar id is 197734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-62819981-G-A is described in Lovd as [Likely_benign]. Variant chr20-62819981-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00963 (1463/151968) while in subpopulation SAS AF= 0.0439 (211/4810). AF 95% confidence interval is 0.039. There are 16 homozygotes in gnomad4. There are 681 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL9A3	NM_001853.4 linkuse as main transcript	c.308G>A	p.Arg103Gln	missense_variant, splice_region_variant	5/32	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.308G>A	p.Arg103Gln	missense_variant, splice_region_variant	5/32		NM_001853.4	ENSP00000496793.1	Q14050
COL9A3	ENST00000452372.2 linkuse as main transcript	c.197G>A	p.Arg66Gln	missense_variant, splice_region_variant	4/12	5		ENSP00000394280.1	Q4VXW1
COL9A3	ENST00000477612.5 linkuse as main transcript	n.304G>A		splice_region_variant, non_coding_transcript_exon_variant	5/12	3
COL9A3	ENST00000489045.5 linkuse as main transcript	n.354G>A		splice_region_variant, non_coding_transcript_exon_variant	4/14	5

Frequencies

GnomAD3 genomes

AF:

0.00965

AC:

1465

AN:

151850

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00256

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.0229

Gnomad SAS

AF:

0.0442

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.0137

Gnomad OTH

AF:

0.00525

GnomAD3 exomes

AF:

0.0136

AC:

3395

AN:

249638

Hom.:

AF XY:

0.0155

AC XY:

2101

AN XY:

135360

show subpopulations

Gnomad AFR exome

AF:

0.00149

Gnomad AMR exome

AF:

0.00269

Gnomad ASJ exome

AF:

0.00219

Gnomad EAS exome

AF:

0.0215

Gnomad SAS exome

AF:

0.0432

Gnomad FIN exome

AF:

0.00228

Gnomad NFE exome

AF:

0.0129

Gnomad OTH exome

AF:

0.00753

GnomAD4 exome

AF:

0.0150

AC:

21913

AN:

1460494

Hom.:

263

Cov.:

AF XY:

0.0158

AC XY:

11485

AN XY:

726570

show subpopulations

Gnomad4 AFR exome

AF:

0.00191

Gnomad4 AMR exome

AF:

0.00271

Gnomad4 ASJ exome

AF:

0.00295

Gnomad4 EAS exome

AF:

0.0188

Gnomad4 SAS exome

AF:

0.0417

Gnomad4 FIN exome

AF:

0.00309

Gnomad4 NFE exome

AF:

0.0147

Gnomad4 OTH exome

AF:

0.0120

GnomAD4 genome

AF:

0.00963

AC:

1463

AN:

151968

Hom.:

Cov.:

AF XY:

0.00917

AC XY:

681

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.00256

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.0232

Gnomad4 SAS

AF:

0.0439

Gnomad4 FIN

AF:

0.00226

Gnomad4 NFE

AF:

0.0137

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.0124

Hom.:

Bravo

AF:

0.00826

TwinsUK

AF:

0.0151

AC:

ALSPAC

AF:

0.0176

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0133

AC:

114

ExAC

AF:

0.0145

AC:

1756

Asia WGS

AF:

0.0290

AC:

101

AN:

3478

EpiCase

AF:

0.0119

EpiControl

AF:

0.0129

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	COL9A3: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2018	This variant is associated with the following publications: (PMID: 30467950) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 07, 2015	- -
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	-	- -

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 05, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;T;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.79

.;T;T

MetaRNN

Benign

0.0064

T;T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

0.51

N;N;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.21

.;N;N

REVEL

Benign

0.16

Sift

Benign

0.22

.;T;T

Sift4G

Benign

0.13

.;T;T

Polyphen

0.022

B;B;.

Vest4

0.11

MPC

0.081

ClinPred

0.013

GERP RS

3.7

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

3.1

Varity_R

0.079

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0045

dbscSNV1_RF

Benign

0.15

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