rs142066316

chr20-62836212-C-Gchr20-62836212-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001853.4(COL9A3):c.1427C>G(p.Pro476Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00407 in 1,613,544 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P476S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0042 (18 hom.)
• Consequence: COL9A3 NM_001853.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.81

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013701469).
• BP6: Variant 20-62836212-C-G is Benign according to our data. Variant chr20-62836212-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 258409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-62836212-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0029 (442/152352) while in subpopulation NFE AF= 0.00456 (310/68036). AF 95% confidence interval is 0.00414. There are 3 homozygotes in gnomad4. There are 193 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A3	NM_001853.4	c.1427C>G	p.Pro476Arg	missense_variant	28/32	ENST00000649368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A3	ENST00000649368.1	c.1427C>G	p.Pro476Arg	missense_variant	28/32		NM_001853.4	P1

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 442 AN: 152234 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00456

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00208 AC: 519 AN: 248964 Hom.: 1 AF XY: 0.00209 AC XY: 283 AN XY: 135256

Gnomad AFR exome AF: 0.000578

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.000600

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00394

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00420 AC: 6130 AN: 1461192 Hom.: 18 Cov.: 33 AF XY: 0.00403 AC XY: 2927 AN XY: 726924

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.000651

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000945

Gnomad4 NFE exome AF: 0.00521

Gnomad4 OTH exome AF: 0.00371

GnomAD4 genome AF: 0.00290 AC: 442 AN: 152352 Hom.: 3 Cov.: 34 AF XY: 0.00259 AC XY: 193 AN XY: 74516

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00456

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00380 Hom.: 0

Bravo AF: 0.00314

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00431 AC: 37

ExAC AF: 0.00177 AC: 215

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00403

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2020	This variant is associated with the following publications: (PMID: 30467950) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 07, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	COL9A3: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 26, 2017	- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
Polyphen		1.0	D;D
Vest4		0.59
MVP		0.96
MPC		0.43
ClinPred		0.017	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.62

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

Other links and lift over

dbSNP: rs142066316; hg19: chr20-61467564;