rs142792529

Positions:

Variant summary

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

The NM_001853.4(COL9A3):c.1816G>A(p.Ala606Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,552,770 control chromosomes in the GnomAD database, including 148 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 0.0090 ( 5 hom., cov: 32)

Exomes 𝑓: 0.012 ( 143 hom. )

Consequence

COL9A3
NM_001853.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.836

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031912327).

BP6

Variant 20-62838713-G-A is Benign according to our data. Variant chr20-62838713-G-A is described in ClinVar as [Benign]. Clinvar id is 258418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-62838713-G-A is described in Lovd as [Likely_benign]. Variant chr20-62838713-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00898 (1367/152300) while in subpopulation NFE AF= 0.0141 (959/68028). AF 95% confidence interval is 0.0134. There are 5 homozygotes in gnomad4. There are 661 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL9A3	NM_001853.4 linkuse as main transcript	c.1816G>A	p.Ala606Thr	missense_variant	31/32	ENST00000649368.1	NP_001844.3
COL9A3	XM_047439893.1 linkuse as main transcript	c.1993G>A	p.Ala665Thr	missense_variant	30/31		XP_047295849.1
COL9A3	XM_047439894.1 linkuse as main transcript	c.1255G>A	p.Ala419Thr	missense_variant	31/32		XP_047295850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL9A3	ENST00000649368.1 linkuse as main transcript	c.1816G>A	p.Ala606Thr	missense_variant	31/32		NM_001853.4	ENSP00000496793	P1

Frequencies

GnomAD3 genomes

AF:

0.00900

AC:

1370

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00347

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00829

Gnomad FIN

AF:

0.0169

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0141

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00869

AC:

1374

AN:

158024

Hom.:

AF XY:

0.00892

AC XY:

742

AN XY:

83196

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.00233

Gnomad ASJ exome

AF:

0.00515

Gnomad EAS exome

AF:

0.000348

Gnomad SAS exome

AF:

0.00780

Gnomad FIN exome

AF:

0.0168

Gnomad NFE exome

AF:

0.0128

Gnomad OTH exome

AF:

0.00495

GnomAD4 exome

AF:

0.0125

AC:

17451

AN:

1400470

Hom.:

143

Cov.:

AF XY:

0.0123

AC XY:

8476

AN XY:

690850

show subpopulations

Gnomad4 AFR exome

AF:

0.00190

Gnomad4 AMR exome

AF:

0.00265

Gnomad4 ASJ exome

AF:

0.00445

Gnomad4 EAS exome

AF:

0.000390

Gnomad4 SAS exome

AF:

0.00816

Gnomad4 FIN exome

AF:

0.0169

Gnomad4 NFE exome

AF:

0.0140

Gnomad4 OTH exome

AF:

0.00930

GnomAD4 genome

AF:

0.00898

AC:

1367

AN:

152300

Hom.:

Cov.:

AF XY:

0.00888

AC XY:

661

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00262

Gnomad4 AMR

AF:

0.00346

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00809

Gnomad4 FIN

AF:

0.0169

Gnomad4 NFE

AF:

0.0141

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.0109

Hom.:

Bravo

AF:

0.00754

TwinsUK

AF:

0.0121

AC:

ALSPAC

AF:

0.0143

AC:

ESP6500AA

AF:

0.00374

AC:

ESP6500EA

AF:

0.0123

AC:

103

ExAC

AF:

0.00533

AC:

526

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	COL9A3: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 27, 2018	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:2

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

May 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

3.2

DANN

Benign

0.79

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.42

.;T

MetaRNN

Benign

0.0032

T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

1.6

L;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.72

.;N

REVEL

Benign

0.18

Sift

Benign

0.57

.;T

Sift4G

Benign

0.53

.;T

Polyphen

0.20

B;B

Vest4

0.21

MVP

0.53

MPC

0.30

ClinPred

0.0057

GERP RS

-0.78

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.016

gMVP

0.35

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